CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

31
CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait

Transcript of CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

Page 1: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

CHEMISTRY 2600

Topic 6 Oxidation and Reduction ReactionsSpring 2008

Dr Susan Lait

2

Oxidation States of Carbon

Carbon can have any oxidation state from -4 to +4 Propose a set of nine molecules (one for each oxidation

state) showing the nine possible oxidation states of carbon

As a general rule increasing the number of bonds to oxygen increases a carbon atomrsquos oxidation state while increasing the number of bonds to hydrogen decreases its oxidation state

3

Oxidation States of Carbon

Because organic chemists care primarily about carbon reactions in which O is added to a molecule or H2 is removed from a molecule are classified as oxidation reactions

Similarly reactions in which H2 is added to a molecule or O is removed from a molecule are classified as reduction reactions

4

Oxidation States of Carbon

Note that functional groups containing carbon with the same oxidation state can be readily interconverted via non-redox reactions A few examples of this include

Conversion of a ketone or aldehyde to a ketal or acetal

Conversion of a nitrile to a carboxylic acid

Conversion of an aldehyde to an imine

5

Oxidation States of Carbon

We also donrsquot generally refer to reactions in which one carbon is oxidized but another is reduced as ldquoredox reactionsrdquo (even though technically they are) A few examples of such ldquonon-redoxrdquo reactions include

Tautomerization of an enol to a ketone

Acid-catalyzed addition of water to an alkene (adding H2 and O)

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 2: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

2

Oxidation States of Carbon

Carbon can have any oxidation state from -4 to +4 Propose a set of nine molecules (one for each oxidation

state) showing the nine possible oxidation states of carbon

As a general rule increasing the number of bonds to oxygen increases a carbon atomrsquos oxidation state while increasing the number of bonds to hydrogen decreases its oxidation state

3

Oxidation States of Carbon

Because organic chemists care primarily about carbon reactions in which O is added to a molecule or H2 is removed from a molecule are classified as oxidation reactions

Similarly reactions in which H2 is added to a molecule or O is removed from a molecule are classified as reduction reactions

4

Oxidation States of Carbon

Note that functional groups containing carbon with the same oxidation state can be readily interconverted via non-redox reactions A few examples of this include

Conversion of a ketone or aldehyde to a ketal or acetal

Conversion of a nitrile to a carboxylic acid

Conversion of an aldehyde to an imine

5

Oxidation States of Carbon

We also donrsquot generally refer to reactions in which one carbon is oxidized but another is reduced as ldquoredox reactionsrdquo (even though technically they are) A few examples of such ldquonon-redoxrdquo reactions include

Tautomerization of an enol to a ketone

Acid-catalyzed addition of water to an alkene (adding H2 and O)

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 3: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

3

Oxidation States of Carbon

Because organic chemists care primarily about carbon reactions in which O is added to a molecule or H2 is removed from a molecule are classified as oxidation reactions

Similarly reactions in which H2 is added to a molecule or O is removed from a molecule are classified as reduction reactions

4

Oxidation States of Carbon

Note that functional groups containing carbon with the same oxidation state can be readily interconverted via non-redox reactions A few examples of this include

Conversion of a ketone or aldehyde to a ketal or acetal

Conversion of a nitrile to a carboxylic acid

Conversion of an aldehyde to an imine

5

Oxidation States of Carbon

We also donrsquot generally refer to reactions in which one carbon is oxidized but another is reduced as ldquoredox reactionsrdquo (even though technically they are) A few examples of such ldquonon-redoxrdquo reactions include

Tautomerization of an enol to a ketone

Acid-catalyzed addition of water to an alkene (adding H2 and O)

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 4: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

4

Oxidation States of Carbon

Note that functional groups containing carbon with the same oxidation state can be readily interconverted via non-redox reactions A few examples of this include

Conversion of a ketone or aldehyde to a ketal or acetal

Conversion of a nitrile to a carboxylic acid

Conversion of an aldehyde to an imine

5

Oxidation States of Carbon

We also donrsquot generally refer to reactions in which one carbon is oxidized but another is reduced as ldquoredox reactionsrdquo (even though technically they are) A few examples of such ldquonon-redoxrdquo reactions include

Tautomerization of an enol to a ketone

Acid-catalyzed addition of water to an alkene (adding H2 and O)

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 5: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

5

Oxidation States of Carbon

We also donrsquot generally refer to reactions in which one carbon is oxidized but another is reduced as ldquoredox reactionsrdquo (even though technically they are) A few examples of such ldquonon-redoxrdquo reactions include

Tautomerization of an enol to a ketone

Acid-catalyzed addition of water to an alkene (adding H2 and O)

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 6: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

6

Reduction Reactions (Hydrogenation)

Wersquove already seen one reaction which organic chemists would consider to be a reduction reaction ndash the nucleophilic addition of hydrogen to a carbonyl (using NaBH4 or LiAlH4 as the source of nucleophilic hydrogen) This was a chemoselective reaction ndash in other words the reducing agent only reduced one functional group (the carbonyl) and left others alone (eg alkenes)

If we want to reduce an alkene or alkyne we need to use a different kind of hydrogen source ndash one which is not chemoselective but will add hydrogen across any bond We want our hydrogen source to be quite literally hydrogen (H2)

Problem The H-H bond is very strong Why is that

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 7: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

7

Reduction Reactions (Hydrogenation)

Solution Use a catalyst to help break apart the hydrogen atoms A transition metal such as Pd or Pt will do this nicely however these metals are extremely expensive and the catalysis only occurs at the surface ndash so coat the metal on something cheap like charcoal to maximise catalytic surface area

Thus the standard choice for a hydrogenation catalyst is 5-10 PdC (since Pt is more expensive than Pd and they work equally well for most reactions) and H2(g) is bubbled through a solution of reactant The catalyst does not dissolve so stirring is essential to keep it suspended

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 8: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

8

Reduction Reactions (Hydrogenation)

The addition of H2 across a bond using a transition metal catalyst like this is always bond using a transition metal catalyst like this is always syn (ie giving the cis product)

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 9: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

9

Reduction Reactions (Hydrogenation)

As noted before this reaction is not particularly chemoselective As long as therersquos a (non-aromatic) bond hydrogen will add

Draw the major organic product of each hydrogenation reaction

O

H2

PdC

EtOH

CN

OH

H2

PdC

EtOH

N H2

PdC

EtOH

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 10: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

10

Reduction Reactions (Hydrogenation)

It is possible to stop hydrogenation of an alkyne at the alkene ndash but only if a poisoned catalyst is used One way to ldquopoisonrdquo a hydrogenation catalyst is to coat the Pd on BaSO4 or CaCO3 instead of charcoal The metal is then treated with for example quinoline and lead(II) acetate to reduce its activity

Hydrogenation of an alkyne with a poisoned catalyst always gives the cis-alkene

NH2

H2

PdC

EtOH

NH2

H2

PdBaSO4

EtOH

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 11: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

11

Reduction Reactions (Hydrogenation)

Azides (R-N3) can also be reduced to amines using H2 and a transition metal catalyst however this is technically hydrogenolysis rather than hydrogenation (because a bond is broken ndash or ldquolysedrdquo)

Treatment of many organic compounds containing heteroatom-heteroatom bonds gives hydrogenolysis

N3 H2

PdC

EtOH

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 12: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

12

Oxidation Reactions (Ozonolysis)

An alkene can be ldquoclipped in halfrdquo to give two carbonyl-containing functional groups via a reaction called ozonolysis (literally reaction with ozone causing a bond to breaklyse)

The three possible sets of conditions for ldquostep 2rdquo are equivalent for the example above but not if there are any hydrogens attached to the alkene If there are then reductive work-up (ZnCH3CO2H or S(CH3)2) gives the aldehyde while oxidative work-up (H2O2) gives the carboxylic acid

OO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

or H2O2

H

HOO

OHOO

1 O3 CH2Cl2 -78 oC+

2 Zn CH3CO2H or S(CH3)2

1 O3 CH2Cl2 -78 oC+

2 H2O2

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 13: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

13

Oxidation Reactions (Ozonolysis)

How does an ozonolysis work Step 1a 13-Dipolar cycloaddition reaction between the

alkene and ozone This gives a very unstable intermediate called a molozonide

Step 1b The molozonide rearranges to a more stable isomer called an ozonide (a kind of cyclic peroxide) This occurs via a retro-13-dipolar cycloaddition followed by another 13-dipolar cycloaddition

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 14: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

14

Oxidation Reactions (Ozonolysis)

Step 2 Work-up At this point the mechanism depends on the kind of work-up Oxidative work-up gives ketones and carboxylic acids (though only one H is replaced by OH in the case of a terminal alkene) Reductive work-up gives ketones and aldehydes

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 15: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

15

Oxidation Reactions (Ozonolysis)

Give the ozonolysis product for each of the following alkenes with (a) oxidative work-up or (b) reductive work-up

1 O3 CH2Cl2 -78 oC

2 S(CH3)2

1 O3 CH2Cl2 -78 oC

2 H2O2

1 O3 CH2Cl2 -78 oC

2 Zn CH3CO2H

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 16: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

16

Oxidation Reactions (Ozonolysis)

Now we can be very clever when coming up with syntheses O

Br

1 O3 CH2Cl2 -78 oC2 S(CH3)2

Mg

Et2O

H2SO4

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 17: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

17

Oxidation Reactions (Dihydroxylation)

Alkenes can also be converted to vicinal diols (ie 12-diols) by reaction with an oxidization agent The two most common choices are

Potassium permanganate (KMnO4) You used this in the CHEM 2000 lab (purple solution for titrating green crystals) Itrsquos relatively affordable but fairly toxic and can be quite a harsh reagent

Osmium tetroxide (OsO4) Donrsquot expect to see this anytime soon in an undergraduate lab OsO4 is dangerously toxic and very expensive Itrsquos also gentler than KMnO4 giving better yields and chemoselectivity (will even oxidize an alkene over an alkyne)

Both oxidizing agents give the syn addition productKMnO4

Na2CO3 H2O 0 oC

OsO4 tBuOOH

tBuOH NaOH

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 18: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

18

Oxidation Reactions (Dihydroxylation)

Whatrsquos the mechanism for dihydroxylation of an alkene with KMnO4

KMnO4

Na2CO3 H2O 0 oC

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 19: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

19

Oxidation Reactions (Dihydroxylation)

This gives us another means by which to cleave an alkene to two carbonyl groups

First dihydroxylate with OsO4 or cold alkaline KMnO4

Then treat the vicinal diol with aqueous sodium periodate (NaIO4)

Unlike ozonolysis this approach only gives aldehydes and ketones from a diol (though NaIO4 will oxidatively cleave between any two oxygenated carbons ndash ketones give carboxylic acids carboxylic acids give CO2)

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 20: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

20

Oxidation Reactions (Dihydroxylation)

How would you prepare each of the following compounds from an alkene containing no oxygen atoms

OH

OH

OHOH

OH OH

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 21: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

21

Oxidation Reactions (Epoxidation)

Itrsquos also possible to convert an alkene to an epoxide (3-atom cyclic ether) by oxidation with a peracid (R-CO3H)

The most common peracids for this purpose are peracetic acid MCPBA and MMPP

OO

O

ClH

OO

O

HO

O

O

H

O

O

peracetic acid MCPBA(m-chloroperoxybenzoic acid)

MMPP(magnesium monoperoxyphthalate)

2

Mg2+

H

HO

H

H

mcpba

benzene

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 22: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

22

Oxidation Reactions (Epoxidation)

The exact mechanism for an epoxidation reaction is not known however it is known that the alkene serves as nucleophile and the peracid as electrophile The mechanism might look something like

What would be the product if exactly 1 equivalent of MMPP was reacted with the diene below

H

HO

O

OH

+

1 equiv MMPP

EtOH

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 23: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

23

Oxidation Reactions (Alcohol to Carbonyl)

Alkenes arenrsquot the only groups we might want to oxidize Itrsquos very useful to be able to convert alcohols to ketones and aldehydes (Just as itrsquos useful to convert ketones and aldehydes to alcohols ndash which wersquove already seen) To do this we need to essentially eliminate H2

Effectively this means that we need to convert the hydrogen atom of the alcohol to a good leaving group (-OH to -OLG) then do an elimination reaction (eliminating H-LG)

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 24: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

24

Oxidation Reactions (Alcohol to Carbonyl)

One way to accomplish this is a Swern oxidation This is a multi-step reaction in which

Dimethylsulfoxide [DMSO (CH3)2SO] is mixed with oxalyl chloride [(ClCO)2] at low temperature (usually in CH2Cl2 solvent)

The alcohol is then added to the reaction flask and allowed to react

Finally triethylamine is added and the flask allowed to warm to room temperature

Between the DMSO and the Et3N this reaction stinks But it works well and itrsquos very gentle so it doesnrsquot destroy other functional groups in the moleculeOH

NC

OH

O

NC

O

H

1 DMSO oxalyl chloride CH2Cl2

2 Et3N

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 25: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

25

Oxidation Reactions (Alcohol to Carbonyl)

So how does a Swern oxidation work Add oxalyl chloride to DMSO

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 26: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

26

Oxidation Reactions (Alcohol to Carbonyl)

Add alcohol

Add Et3N

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 27: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

27

Oxidation Reactions (Alcohol to Carbonyl)

There are a variety of other ways to convert alcohols to carbonyl groups (aldehydes ketones or carboxylic acids) ndash most of them involving chromium

1deg alcohols to aldehydes (2deg alcohols to ketones) PDC (pyridinium dichromate)

PCC (pyridinium chlorochromate)

Collins oxidation (2 1 pyridine CrO3)

Swern oxidation

1deg alcohols and aldehydes to carboxylic acids (2deg alcohols to ketones)

Jones oxidation (CrO3 in H2SO4 = H2CrO4) KMnO4 (not cold)

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 28: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

28

Oxidation Reactions (Alcohol to Carbonyl)

Give the product for each of the following reactions

OHCrO3(pyr)2 CH2Cl2

Br

Br

OH

OHPCC CH2Cl2

heat

OHCrO3 H2SO4

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 29: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

29

Summary of Reactions of Alkenes (Revisited)

CH3

X

CH3

X OH

CH3

X

OH

CH3

X

CH3CH3

OH

H

OH

CH3

OH

CH3

O

CH3

X2

H2O

X2

H2SO4

H2O

HX1 BH3 THF2 H2O2 NaOH3 H2O

OsO4

RCO3H

(or cold dilute KMnO4base)

H2 PdC

AND ozonolysis cleaves alkene to give two carbonyl groups

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 30: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

30

Putting It All Together

One of my tasks as a PhD student was to put together a synthesis of the amino-alcohol above On the last assignment you saw the key step Now letrsquos work through how I got therehellip

NH2OH

H

BrBr

O

O

Mg

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

H+

THF

polar solventheat

1 DMSO (COCl)2

2 Et3N

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H

Page 31: CHEMISTRY 2600 Topic #6: Oxidation and Reduction Reactions Spring 2008 Dr. Susan Lait.

31

Putting It All Together

NH2OHHCl

Irsquove simplified the reaction conditions for some steps but theyrsquore all reactions you know

bleach

H2O CH2Cl2

CH2Cl2

H

N O

C

N+

O

(reacts immediately bond angles not even remotely accurate)

LiAlH4

THF

NH2OH

H