Organic molecules with functional groups containing oxygen

alcohols

carboxylic acids

aldehydes

ketones

C,H

X

X =

X =

X = C

O

C

H

O

C

OH

O

OH

X =

Key Skills

1. Dealing with structures (Bruice 1.4)

We need to understand the following concepts:

• Valency: the number of bonds that an atom must have

eg carbon: 4; hydrogen: 1; oxygen: 2

• Bond Concept: a pair of electrons C C

H

H

H

H

H

H

C CC C

To break a bond, the electron pair has to move

away from the space between the atoms

To make a bond, a pair of electrons has to

move into the space between the atoms

OH

• Drawing structures: we can represent a molecule in a variety of ways

Example: ethanol, C2H6O

Never!! -unless you mean

1,1,2,2-tetramethylpropanol!

A bit long winded – but good if you want to use

the structure in a mechanism

Correct –useful if

space is an issue

Compact –it is the

standard for large

molecules

CH3

CH2

The ability to “read” and draw structural formulae is an absolutely essential skill!

C C OH H C C OH

H

H

H

HH3CCH2OH

CH3 CH2 OH

OH

OH

OH

Problem

How many hydrogens are on each of the carbons indicated below?

A very, very, very, common mistake!

OH

≠

• What is the molecular formula of each of the above molecules?

• How many hydrogens are on each of the carbons?

• What is the name of each compound?

• Is there any other way of drawing the first structure?

2. Dealing with mechanisms (Bruice 1.18, 3.6)

• Most reactions involve intermediates, the nature of which determine the type of mechanism involved

• Reactions can involve a neutral intermediate with an unpaired electron (a radical) or a charged intermediate (a cation (+) or an anion (-))

productintermediatereactant

• A mechanism is a description, in terms of the electrons involved, of how the reactant molecule(s) changes into the product molecule(s). “Curly arrows” are used to show how the electrons move during the change.

• The arrows are double headed in this case, indicating the movement of a pair of electrons• The arrows begin at a definite pair of electrons - a bond or a lone pair –and move towards a positive charge• If they move into the space between two atoms, a bond is formed• If they move out of the space between two atoms, a bond is broken

• If a new bond is formed with a neutral atom, another bond involving that atom has to be broken

H C C O

H

H

H

H

H2SO4

H

H

H H C C O

H

H

H

H

H

H

C C

H

H

H

H

+ H2O+ H

≡Example: a reaction mechanism involving charged intermediates

• If an atom gains an electron, it acquires a negative charge; if an atom loses an electron, it acquires a positive charge

The Chemistry of Alcohols

RO

Hδ+

δ−

Functional Group

HO

Hδ+

δ−

General Alcohols

Key Point: alcohols and water contain the same functional group (FG)

C,H

functionalgroup

R

Famous Alcohols1. Ethanol

H C C O

H

H

H

H

H OH

C C

H

H

H

H

+ H2O H3CCH2OH

H3PO4 oncharcoal

300°C

or

• World Production (2006): 51 gigalitres (5.1 x 1010litres) – 69% from the US/Brazil

• Structure

• Methods of Production

(a) Hydration of ethene: production of ethanol for use as an industrial feedstock

H3CCH2OH or

gas phase reaction

crude oil

ethanol produced in this way is a petrochemical: non-renewable/not

sustainable

(b) Fermentation

+ 2CO2C6H12O6yeastno O2

H3CCH2OH

fermentable sugars such as glucose, fructose or sucrose

(C12H22O11)

sugar cane

(Brazil)

corn (starch) (US):

production of ethanol a a fuel

barley:production of ethanol as a

beverage

malting -involves the

enzyme amylase

H2SO4

(c) Cellulosic ethanol

Cellulose is a glucose polymer which makes up 38% of all plant matter but which cannot be fermented directly

materials such as straw, sawdust, bagasse (residue after extraction

of sugars from sugar cane), switchgrass (an “energy crop”)

fermentable sugar

cellulose glucose

enzymic hydrolysis

cellulase

(d) Bioethanol production in Ireland

The fluid left when the solids are removed from the milk during the making of cheese is called whey and contains fermentable sugars. This is currently the source of all bioethanol produced in Ireland. However the amount of bioethanol available from this source would not be sufficient to satisfy the demand for it as a fuel.

The Food vs Fuel Debate: Is bioethanol a green fuel? ≡ Is bioethanol a sustainable source of energy?

fertilizer (natural gas (CH4) is one of the raw materials used

in its manufacture), energy used (machinery/transport/

processing)

ethanol energy + CO2corn

sunlight and CO2

Key question: what is the “energy return on energy invested” - EROEI

The value of corn as an energy crop is marginal as

its EROEI = 1.34

• Corn

• Sugar cane Much better: EROEI ≈ 8

• Best solution for corn: use grain as food and the straw to produce cellulosic ethanol

2. Methanol

• Structure C O

H

H

HH H3COH

CH4 + H2O

10 - 20 atm850°C

Ni catalystCO + 3H2

or

• Method of Production

50 - 100 atm250°C

Cu, ZnO/Al2O3

CO + 3H2 H3COHStage 2

Stage 1

mixture is known as syngas

steam-methane reforming

methanol is thus a petrochemical

• Uses

(a) Industrial feedstock

(b) Denaturing ethanol: Methanol is toxic - it is added to ethanol to make it unfit for consumption; this mixture is called methylated spirits

3. Ethylene glycol (1,2-ethanediol)

• Structure

O C C O

H

H

H

H

HHHO

OH

HOCH2CH2OH

HOOHC C

H

H

H

H Ag/Al2O3

200-300°CO2, 1-2 atm

C C

H

H

H

H

H2SO4, H2OO

or

or

• Manufacture

crude oil

ethylene oxide – an epoxide or oxirane

once again this product is a

petrochemical

• Uses: ethylene glycol is used as antifreeze

OH

H3C CH3

CH3H

H3C CH3

CH3

OH

CH3CH3

CH3

OH

4. More complicated alcohols

geraniolrose oil

(R)-(+)-citronellollemon grass oil

(1R,2S,5R)-(-)-menthol peppermint oil

Something that is most certainly not an alcohol!!

phenol cyclohexanol

OH OH

≡ ≡

OHCheck the

number of Hs on each C!

Not an alcohol

An alcohol

Nomenclature of alcohols (Bruice 2.6)

The IUPAC name of an alcohol is based on the name of the alkane from which it comes, using the name ending -ol

• Identify the longest continuous chain of carbon atoms in the molecule → parent name

• Change the name ending from –e to –ol

• Giving the –OH group the lowest number possible, number the position of attachment of side chains

HO

1

25

HO

1

2

6

OH

1(6)6(1)

3(4)

pentan-2-ol or2-pentanol

4-methylhexan-2-ol or 4-methyl-2-

hexanol

hexan-3-ol or3-hexanol

Examples

Cyclic alcohols: uses the name of the cycloalkane on which they are based

OH

HO

1

OH3

Alcohols which have more than one OH group: named using the basic rules and the ending diol, triol, etc., as appropriate

HOCH2CH2OH

cycloheptanol

1,3-butanediol orbutane-1,3-diol

1,2-ethanediol orethane-1,2-diol(trivial name:

ethylene glycol)

Classes of alcohol

The division is based on the number of carbons which are attached to the carbon (*) bonded to the functional group

Primary Alcohol (1°)- attached to one

carbon

Secondary Alcohol (2°)- attached to two carbons

Tertiary Alcohol (3°)- attached to three

carbons

methanol

H3C CH2 OH∗ ∗H3C

CH3C

OHH3CH3C

CHH3C

OH∗

H3C OH

Physical Properties (Bruice 2.9)

Key Point

1. Solubility of alcohols in water

alcoholsolubility

(g/100cm3)

R O Hδ− δ+

H O Hδ−

δ+ δ+very polar

∞

∞2.3

0.05

non-polarpolar Key

concept: like

dissolves like

H3C OH

H3CCH2 OH

H3CCH2CH2CH2CH2 OH

H3CCH2CH2CH2CH2CH2CH2CH2 OH

There is competition between the polar and non-polar parts of the molecule

13888

11874

9760

BP (°C)MMMolecule

CH3CH2CH2CH2 O Hδ+δ−

CH3CH2CH2 O Hδ+δ−

CH3CH2CH2CH2CH2 O Hδ+δ−

2. The effect of alcohol structure on boiling point (BP)

(a) Boiling point / molecular mass relationship

The BP increases as the MM increases

(b) Boiling point / FG relationship

11874Hydrogen

7672Dipolar

3672VdW

BP (°C)MWIntermolecular BondingMolecule

CH3CH2CH2CH2 O Hδ+δ−

CH3CH2CH2Cδ+

δ−O

H

CH3CH2CH2CH2CH3

The BP increases as the strength of the intermolecular bond increases

General Methods of Synthesising Alcohols1. Acid catalysed hydration of alkenes (see section on Alkenes; Bruice 4.5)

C C

H

H

H

HH2SO4

H2OH C C O

H

H

H

H

HBasic Reaction

Mechanism

H2SO4

H

C C

H

H

H

H≡ H2O

H C C

H

H

H

H

H C C O

H

H

H

H

H

H

H C C OH

H

H

H

H

H +

key intermediate: carbocation

Problem

The acid catalysed hydration of the following alkene could, in principle, lead to the formation of two products:

H2C CCH2CH2CH3

CH3

2. Using the mechanism on the previous page as a template, draw a mechanism for the formation of the two products

3. Which of the two will be the major product? Explain your answer.

The reaction proceeds in accordance with the Markovnikov Principle: the hydrogen adds to the carbon which already has the

most hydrogens. The product formed is said to be the “Markovnikov product “

1. Draw the structures of the two products

2. Hydroboration of alkenes (see section on Alkenes; Bruice 4.10)

Basic Process

H2C CH2BH3 H3C CH2 3B

NaOH/H2O2 H3C CH2 OH

We are interested in this reaction as a way of making alcohols and so we need to know that the reaction gives an anti-Markovnikov product:

H3CHC CH2(1) BH3, THF

(2) NaOH/H2O2CH3CH2CH2OH

hydrogen adds here

Problem: suggest a synthetic route to each of the following alcohols

The following problems relate to either acid catalysed hydration or hydroboration-oxidation

OH

??

?? H3CCHCH2CH2CH3

OH

??

OH

2 routes

Problem: draw the structure of the product formed in each of thefollowing reactions:

?H2SO4, H2O (1) BH3

(2) NaOH, H2O2

?

3. Substitution reactions of alkyl halides (haloalkanes) (Bruice 8.5)

leaving group

An example ofnucleophilic substitution

Br

NaOH

H2O

OH

Na Br+δ+δ−

Na OH≡

nucleophile

Problem: write a simple curly arrow mechanism for the above reaction

H3CH2C ClExperimentally:

heat

haloalkane: a liquid NaOH solution

electrophilic carbon

4. Redox reactions (Bruice 10.5, 19.3, 19.1)

Alcohols, ketones/aldehydes and carboxylic acids can be interconverted using redox reactions

C

O

OH

H3C C

O

H

H3C CH3LiAlH4 LiAlH4 CH2 OH

C

O

CH3

H3CLiAlH4

C OH

H3C

H3C H

carboxylic acid aldehyde 1° alcohol

red red

ox ox

2° alcoholketone

ox

red

common reducing agent: lithium aluminium hydride

commonoxidising agent:

sodium dichromate

These reactions allow

some of the most important

functional groups to be

interconverted

Na2Cr2O7 Na2Cr2O7

Na2Cr2O7

Overall: using redox reactions to synthesise/prepare alcohols

aldehyde 1° alcohol

ketone 2° alcohol

Discussed in more detail in the “Aldehydes and Ketones” section below

5. Grignard Reaction

Victor Grignard was born in Cherbourg in 1871, the son of a sail maker. He did his PhD in Lyons, working with Philippe Barbier who suggested that he study organomagnesium compounds. He published his thesis in 1900 and over the succeeding 10 years he studied the applications of organomagnesium reagents in synthesis. He was so successful that he was awarded the Nobel Prize for Chemistry in 1912. Today, the terms organomagnesium reagent and Grignard Reagent are used interchangeably.

Grignard Reactions are important because they are a very good way of making the C-C bonds which provide the framework for all organic (carbon-based) molecules

What led to Barbier’ssuggestion?

magnesiummetal

magnesiumdissolves

reaction

What’s in the solution and what properties

does it have?

H3C–Br

H3C–Br + Mg → H3C–MgBr

organometalliccompound

organomagnesium compound ≡ Grignard Reagent

δ+δ-

haloalkane

solvent such as dry diethyl ether

H3CCH2-O-CH2CH3

methylmagnesium bromide

How are Grignard Reagents formed and why use diethyl ether (Et-O-Et) ?

H3C Br

H3C Mg Br

EtO

Et

EtO

Et

H3C Mg Br

surface of piece of Mg

Grignard Reagent (GR) forms on the surface

The magnesium only has 4 electrons. This is made up to 8 by theformation of coordinate bonds by two solvent molecules. The solvated GR is now soluble and moves away from the surface

the surface is now free to react with more haloalkane

haloalkane adsorbs onto the Mg surface

Problem Tetrahydrofuran (THF) is also a frequently used solvent for GRs. Why?

Why is the use of a “dry” solvent essential?

H3C MgI + H2O CH4 MgI(OH)+

We have made the GR to react it with something. Water in the solvent (or indeed in any the reactants) will react instead with the GR,

converting it rapidly to the corresponding alkane.

Problem The GR/H2O reaction belongs to what class of reaction? (Hint: what is being transferred in the course of the reaction?)

Reactivity of Grignard Reagents

What sort of reactions would we expect for GRs?

Key bond in the GR – always draw the GR in this way so as to emphasise the importance of the Mg-C bond

The carbon has a partial negative charge because of the

electronegativity difference between carbon and

magnesium. It has carbanion character and acts as a

nucleophile.

The GR will thus react with molecules containing an electrophilic atom – an atom with a positive or

partial positive charge, eg a carbon with a δ+ charge

The introduction of a Mg atom inverts the polarity present in the haloalkane we started with:

H3C MgIδ+δ−

H3C Iδ+ δ−

What sort of molecules do GRs react with?

CH

O

C

O

O C OO

C

O

O

N

δ+ δ+δ+

δ+

δ+

δ+

δ−δ−

δ−

δ− δ−δ−

δ−

aldehydes ketones

epoxides(oxiranes)

C-N multiple bonds

carbon dioxide

esters

The molecules in red all react with Grignrd Reagents to give alcohols

H3CC

CH3

OH3C MgBr

δ+δ−δ+

δ−

H3CC

O

H3C CH3

MgBr H3CC

OH

H3C CH3

magnesiumsalts+

H2SO4

Mg + H3CBrStage 1

Stage 2

Using the Grignard Reaction to make alcohols

• Tertiary alcohols: the reaction of a GR with a ketone

Acid (H+) is added at the end of the reaction to convert the alcohol salt to the alcohol

Although some simple GRs (such as this one) are

available commercially, we usually have to

make them

The reaction is an example of a

nucleophilic addition

3° alcohol

• Tertiary alcohols: the reaction of Grignard Reagents with esters

δ+δ−+ C

HO

H3CH2CH3CCH2 C

O

OCH3

δ−

δ+ Mg Br2

This reaction involves 2 moles of GR and the introduction of two”R” groups from the GR

This reaction can be used to make any 3° alcohol in which two of the R groups are the same

Mechanism of the reaction of a Grignard reagent with an ester

Problem: write a simple mechanism for the second stage of the reaction

Problem: the 3° alcohol shown can be prepared by the reaction of H3C-MgBr with (a) a ketone and (b) an ester. Provide structures for both starting materials

Ph C

OH

CH3

CH3

H3CCH2 C

O

OCH3

Ph

MgBrδ+

δ+

δ−δ−

H3CCH2 C

O

OCH3

MgBr

Ph H3CCH2 C

O

Ph

Ph MgBr

H3CCH2 C

OH

Ph

Ph

H3CO MgBr+

• Secondary alcohols: the reaction of a GR with an aldehyde

HC

CH3

O

MgBrδ+δ−δ+

δ−H3CH2C+

CH2CH3

CHO

CH3H2°

alcohol

Problem: using the mechanism on the previous page as a template, write a simple mechanism for this reaction

• Primary alcohols: the reaction of a GR with the simplest aldehyde, methanal (formaldehyde)

HC

H

OMgBrδ+δ−δ+

δ−H3CH2C+

CH2CH3

CHO

HH1°

alcohol

aldehyde

methanal

Problem: using the mechanism on the previous slide as a template, write a simple mechanism for this reaction

• Primary alcohols: the reaction of Grignard Reagents with epoxides(oxiranes)

δ+

δ−

H3CH2C MgBr

O

H2C CH2

δ− δ+

H2C CH2

O

H3CH2C

MgBrH2C CH2

OH

H3CH2C

H

1° alcohol

This reaction is regiospecific because the following epoxide gives a product resulting from attack of the nucleophilic GR at the less sterically hindered carbon of the three-membered ring

Ph MgBrO

HC CH2

δ− δ+CH CH2

OH

PhH3C

δ+ δ+H2C CH

OH

H3C Ph

H3C

+

not formed

formed

Reactions of Alcohols: overview

RO

Hδ+

δ−

acidic hydrogen

nucleophilic oxygen

Reactions of alcohols

weakly acidic hydrogen

HO

H + Na 1/2 H2↑ + Na OH

H3CO

H + Na 1/2 H2↑ + Na OCH3

CO

HH3CCH3 CH2 OH

Na2Cr2O7

2. Redox reactions (see “General Methods of Synthesising Alcohols; Reaction 4” above)

CO

CH3

H3CC OHH3C

H3C H

Na2Cr2O7

1° alcohol

2° alcohol

aldehyde

ketone

1. Water like reactions

Problem Assign an oxidation to the indicated C-atom and confirm that this changes during the reaction.

ox

ox

3. Acid catalysed elimination reactions (dehydration) (see “Alkenes”above)

H C C O

H

H

H

H

H2SO4

H

H

H H C C O

H

H

H

H

H

H

C C

H

H

H

H

+ H2O+ H

≡

• This elimination can also be heterogeneously catalysed by alumina (Al2O3) • The acid catalyst converts a poor leaving group (OH) into a good leaving group (H2O)

• This mechanism is known as an E2 mechanism as the alkene π bond forms and the bond to the leaving group beaks, at the same time. It is the counterpart of an SN2 reaction

• This is an elimination reaction: a small molecular unit (H2O) is lost and a multiple (double) bond is formed

Relative ease of dehydration R C

R

R

OH R C

H

R

OH R C

H

H

OH> >

2°3° 1°

3° and 2° alcohols are easier to dehydrate because they can do so via a different route, the E1 mechanism. Paralleling the SN1 mechanism this involves the formation of a carbocation intermediate:

H3C CH

OH

CH3H2SO4

H

H3C C O

H3C

H

H

H

C C

CH3

H

H

H

+ H2O

+ H

H2C CH

H3C

H2°

The intermediate formed is a 2° carbocation. A 3°alcohol would form an even more stable 3°carbocation and so is more reactive. A 1° alcohol will not react by this E1mechnism as the 1°carbocation it would give is too unstable to form; a 1° alcohol will react via the E2 mechanism.

4. Conversion to haloalkanes

OH

HI

I

+ H2O

H3C CH

OH

CH3HBr

H3C CH

Br

CH3

+ H2O

H3CCH2CH2CH2OHPBr3 H3CCH2CH2CH2Br

• These are substitution reactions. 2° and 3° alcohols react via an SN2 mechanism, whereas 1° alcohols follow an SN2 route

• Phosphorous trihalides are efficient alternatives to the hydrogen halide

Problem Write a simple SN1 mechanism for the reaction of 2-propanol and HBr shown above.

5. Reaction of alcohols with carboxylic acids: ester formation

H2SO4+ H2OH3C C

O

OH

+ H3CCH2OH H3C C

O

OCH2CH3

δ+

δ−

More information on this very important reaction is given in the section on Carboxylic Acids below

Ketones and Aldehydes: the chemistry of the carbonyl group

Functional GroupKetones

Key Points

• the chemistry of ketones and aldehydes is the chemistry of thecarbonyl group and so they are considered together

C,H

functionalgroup

RR

C

R

Oδ−δ+

AldehydesH

C

R

Oδ−δ+

• the only real difference between the two is in terms of oxidation – the aldehyde group is the most easily oxidised FG of all. Oxidation involves the H-atom attached to the carbonyl group and so we can include this atom in the FG of the aldehyde

Famous aldehydes

C

O

H

OCH3

HO

O

CH H

O

CH3C H

Famous ketones

vanillin methanal (formaldehyde)

ethanal(acetaldehyde)

air pollutants: photochemical smog

propanone(acetone) solvent

camphor

O

CH3C CH3

O

CH3H3C

H3C

O

CH3

CH2H3C

O

CH3

CH2H3C

(R)-(-)-carvonespearmint oil

(S)-(+)-carvonecaraway seed oil

All the usual rules apply

• Name ending for aldehydes: al

• The carbon of the aldehyde FG is always given the number 1

• Name ending for ketones: one

• The carbon of the ketone group is given the lowest number possible

Nomenclature of ketones and aldehydes

CH

O

H3C HC

H2C

CH

OCH3

HC

CH

O

O

2-hexanone

3-methylbutanal butanedial

7-methyl-4-octanone

not 2-methyl-5-octanone3-methylcyclobutanone

hexanal

Examples of aldehyde nomenclature

Examples of ketone nomenclature

C

O

H3CCH2

H2C

C

H2C

O

CH2

CHCH3

CO

H3C

CH3

Physical Properties of aldehydes and ketones

Solubility in water

• As with alcohols there is competition between the polar and non-polar part of these molecules

Boiling Point (BP)

Intermolecular bonding (----) is of the dipolar type => BPs are higher than for alkanes (VdW) but not as high as for alcohols (H-bond) (see table in “Alcohols” section )

R

C

(H)R

Oδδ

polar

non-polar

• If R is small (few C/H): very soluble in water

• As the number of C/H increases, the solubility decreases

R

C

(H)R

Oδ δ

R

C

(H)R

O

δ

δ

Preparation of aldehydes and ketones

Redox Reactions

Oxidation of alcohols (see “Preparation of Alcohols” above)

2° alcohol → ketone K2Cr2O7

OOH

Na2Cr2O7

H3CCO2H

Ketones

Aldehydes

1° alcohol → [aldehyde] → carboxylic acid K2Cr2O7 K2Cr2O7

The problem here is that as aldehydes are so easily oxidised, it is difficult to stop the reaction at the aldehyde stage. Special reagents/conditions have to be used to prevent the aldehyde being converted to the carboxylic acid

K2Cr2O7

One approach is to make use of the fact that the BP of an aldehyde is lower than that of the alcohol from which it comes. A simple aldehyde such as ethanal can be distilled out of the reaction mixture as it is formed and before it can be oxidised further

CH3 CH2 OH CH3 C

O

H

CH3 C

O

H

K2Cr2O7

distilled out

Reactions of ketones and aldehydes

General Expectations

C

O

H

δ+

δ−

α

The hydrogen atoms on the α-carbon are weakly acidic. They can be removed by a strong base to give a

carbanion (C-)

Electrophilic carbon which can be attacked

by nucleophiles resulting in

nucleophilic addition

Chemistry of the carbonyl group: (1) nucleophilic

addition to carbonyl group and (2) carbanion based

reactions at α-carbon

Problem: (a) what sort of alcohol is formed from the reaction of a ketone with a GR

(b) provide an example of this reaction

Problem: (a) what sort of alcohol is formed from the reaction of methanal with a GR

(b) provide an example of this reaction

(c) write out the mechanism of the reaction you provided

Relative reactivity of aldehydes and ketones in terms of nucleophilic addition

• The process involves a nucleophile attacking the electrophilic carbon of the carbonyl group

• The larger the δ+ charge on this carbon, the more attractive it is to the nucleophile and the more reactive the ketone/aldehyde.

• Large groups attached to the carbonyl carbon block the approach of the nucleophile and so reduce reactivity for steric reasons: aldehydes are more reactive than ketones for steric reasons

R

O

H

< δ+

δ−Nu

R

O

R

< <δ+

δ−Nu Aldehydes are thus more reactive than

aldehydes for electronic reasons

R groups such as CH3are electron donating groups (induction).

This reduces the size of the δ+ charge on the C-atom of the carbonyl group

2. Nucleophilic addition with primary amines and derivatives of primary amines

The reaction of ketones/aldehydes with 1° amines: imine formation

N

H

H

N

R

H

N

H

H

N

R

R

H R R Ramines

Secondary (2°)

H3CC

H3CO

δ+ δ−HN

R

H+

H3CC

O

H3C N H

R

H H3CC

H3CN

RH2O

H++

nucleophileelectrophile

nucleophilic addition

eliminationImine (Schiff

base)

Primary (1°)

Tertiary (3°)

Ammonia

Overall: nucleophilic addition-elimination

Nucleophilic Addition1. Grignard Reaction (see “Preparation of Alcohols” above)

2°alcoholaldehyde

HC

H3CH2CO

HC

Ph

O

MgBrδ+δ−δ+

δ−H3CH2C+

CH2CH3

CHO

PhH

HC

Ph

O MgBrδ+

δ−δ+

δ−

CH2CH3Key step in the nucleophilic addition mechanism

electrophile nucleophile

Problem: Write out the mechanism in full for this aldehyde /GR combination:

MgClHCH2CH3C

H3C

H3CC

H3CN

R

H

+ H2O

H3CC

H3CN

R

+ H

Mechanism for imine formation

H+: acid catalystOverall this is a nucleophilic addition-elimination reaction

H3CC

O

H3C N H

R

H

H

H3CC

OH

H3C NH

R

H

H3CC

O

H3C N H

R

H

+ H

H3CC

H3CO

H

H3CC

H3COH

HNR

H

1 2 3 4 5 6 7

Evidence for the proposed mechanism: effect of pH on the reaction of acetone with methylamine

pH

second order rate constant, k

Reaction slow: not enough H+ to protonate the

neutral tetrahedral intermediate. This is required so that

a good leaving group (H2O) is

availableReaction slow: too

much H+, resulting in protonation of the

amine, removing its nucleophilic properties:

RNH2 H+ RNH3+

Related reactions of 1° amines

(H)RC

RO

δ+ δ−NH2+ H2O+NH2

(H)RC

RN

NH2

(H)RC

RO

δ+ δ−NH2+

HN

O2N

NO2 NHN

O2N

NO2C

R

(H)R

(H)RC

RO

δ+ δ−NH2+ + H2OOH

(H)RC

RN

OH

hydrazine a hydrazone

2,4-dinitrophenylhydrazine a 2,4-dinitrophenylhydrazone

hydroxylamine an oxime

Problem: using H2O as B write out a detailed mechanism for the reaction of the following:

HC O NH2CH3

H2CH3CC

H3CO H2N

CH3CH2

CPh

NHO

Problem: Write out the structure of the product formed by the following:

Problem: Draw the structures of the ketone, or aldehyde, and amine derivative that would be required to form the following:

H3CC

HN

4. The reaction of aldehydes and ketones with hydride ion: reduction(see “Preparation of Alcohols” above)

The reduction of the carbonyl group in an aldehyde or ketone using metal hydride reagents, such as sodium borohydride or lithium aluminium hydride, is effectively a nucleophilic addition process in which the nucleophile is the hydride ion, H-.

H3CH2CH2CC

O

H H3CCH2CH2CH2 OH(a) NaBH4

(b) H+

O HHO

(a) LiAlH4

(b) H+

Mechanism of hydride reduction of ketones/aldehydes

RC

O

R

Hδ+

δ−

H+

RC

R

O H

RC

R

HO H

LiAlH4 ≡ HNaBH4 ≡Key Point: sodium borohydrideand lithoum aluminium hydride are synthetically equivalent to a hydride ion

Mechanism

nucleophile

The reduction reaction fits in with the nucleophilic addition group of reactions

5. The reaction of ketones and aldehydes with alcohols

This is a reaction with considerable biological importance

HC

R

O

+ H3COHδ+

δ− OH

C OCH3H

R

H+ H+OH

C OCH3H

R

a hemiketal

an acetal

RC

R

O

+ H3COHδ+

δ− OH

C OCH3R

R

H+ H+OH

C OCH3R

R

a hemiacetal

a ketal

So how does this reaction happen?

hemiacetal

acetal

RC

O

H

H+

δ+

δ−

RC

O

H

H

OH3C

R C

OH

H

OH3C H

R C

OH

H

H3CO

+ H+

R C

OH

H

H3CO

H

HC

H3CO

R

H

OCH3H

R C

OCH3

H

H3CO

H

R C

OCH3

H

H3CO + H+

hemi => half

So why are these reactions important?

Carbohydrates are extremely important molecules with a very wide range of biological activity. Their behaviour depends on the fact that they can exist in both an open chain and a ring form.

Problem: write out the mechanism for the reaction of ethanol with ethanal

Problem: write out the mechanism for the reaction of methanol with acetone (propanone)

The difference between intermolecular and intramolecular reactions

Intermolecular reaction: the reactions on the previous slide are intermolecular as the interacting functional groups are in separate, independent molecules

Intramolecular reaction: the reaction involves functional groups which are in the same molecule

chain of atoms connecting the two functional

groups

reaction

new bond formed

In most cases intramolecular reaction lead to the formation of a ring

XY

XY

Problem: in terms of thermodynamics, intramolecular reactions enjoy a certain advantage. What is it?

Ring and open chain forms of D-glucose

C

C

OH

OHH

C HHO

C OHH

C OHH

CH2OH

O

H

HO

H

HO

H

OHOHH

H

OH

O

H

HO

H

HO

H

HOHH

OH

OH

open chain form

α-D-glucose β-D-glucose

intramolecularhemiacetalformation

RO

H

OHR

RO

OH

HR

The formation of the ring form of a carbohydrate is an example of hemiacetal formation

Reactions at the α-carbon: carbanion/enolate chemistry

Key point: α-hydrogen atoms are acidic

enolatecarbanion

resonance hybrid

most important resonance form: negative charge on

electronegative oxygen

The α-hydrogens are acidic because the anion formed is resonance stabilised

H2C C

O

CH3

HB

H2C C

O

CH3 H2C C

O

CH3

H2C C

O

CH3

≡base

H3C C

O

CH3 H2C C

OH

CH3

Where does the term enolate come from?

Ketones (and aldehydes) exist as an equilibrium mixture of two isomeric forms which differ only in the position of a hydrogen atom. These isomers are known as tautomers and the equilibrium as a tautomeric equilibrium

keto form enol form

en

ol

• Most simple ketones/aldehydes contain only a tiny amount of the enol form (~1%)

• An enolate is the negative ion obtained by removing a proton from an enol

1. α-Alkylation of ketones and aldehydes

Ketones and aldehydes are not strong acids and in most cases NaOH and related bases are not basic enough to remove an α-H.

A commonly used strong base is lithium diisopropylamide (LDA)

LiN ≡ R2N Li

Basic α-alkylation reaction R

O

R

H

LDA

R'HalR

O

R

R'

α-Carbon Reactions of Ketones and Aldehydes

Mechanism of α-alkylation

LiR2N

O

H

OCH3I O

H3C

+ R2NH

+ ILi

substitution reaction

C-C bond formed

The carbanions/enolates formed by abstraction of an α-H atom can also get involved in addition reactions

3. The aldol addition reaction

In this reaction the carbonyl group of an aldehyde or ketone provides both the electrophile and the nucleophile component

H

O

R

H

H

O

R

H

δ+

δ−

H

O

R

nucleophile electrophile

The Aldol Reaction illustrates how versatility of the carbonyl group in terms of reactivity and explains why it is the most synthetically important of all the functional groups

Typical Aldol Reaction

CH

O

H3C CH

O

HC

CH3

OH

H3CNaOH

CH

O

C

CH3

H3C

+ H2O

2

H

Things to note:

• It’s a dimerization

• It’s a C-C bond forming reaction

• The name of the reaction comes from the nature of the product – an aldol

• Ketones react more slowly because the reaction involves a nucleophilic addition to the C=O of one of the reacting units (see above)

• The product is easily dehydrated as this results in the formation of a very stable conjugated system – a double-single-double bond arrangement. This dehydration often occurs under the reaction conditions used for the Aldol Addition Reaction – so we never see the aldol.

ald

ol

unit 1 unit 2 conjugated system

Mechanism of the base promoted Aldol addition reaction

H2CC

H

O

OH

H

H2CC

H

O

H3CC

H

O

δ+

δ−

CH2

CH

O

CH

O

H3C CH2

CH

O

CH

OH

H3C

H OH

+ HOnew C-C bond

aldol

OH

HC

CH

O

HC

OH

H3C

H

CC

H

O

CH3C

H

H

+ H2O + HO

CC

H

O

CH

H

CH3

+

The overall process is known as the Aldol Condensation if dehydration occurs at the same time

Condensation Reaction: two functional groups combine, eliminating a small molecule – often water

conjugated systemtrans isomer major product

cis isomer minor product

Problem: write down the structure of the aldol addition product that would be formed by the following

O

H

CH3CH2

O

CH2CH3

Problem: what aldehyde or ketone would be required to make the following:

2-ethyl-3-hydroxyhexanal

H3C

Ph

H

O

Ph

The Mixed (Crossed) Aldol Reaction

All of the Aldol Reactions considered so far have been dimerizations – they have involved a molecule reacting with another molecule identical molecule

A + A → 2A

So wouldn’t the range of molecules we could make with this reaction be greatly increased if we reacted a ketone/aldehyde with a ketone/aldehyde with a different structure?

H3C

O

H H3C

O

HH3C

O

H

HO CH3+

- H2O H3C

O

H

CH3

In principle yes – but there is a problem with such mixed (crossed aldol reactions

The problem with Mixed Aldol Reaction

Most Mixed Aldol Reactions result in a complex mixture of products and so are of no synthetic value. Why?

There are really 4 reactants involved in the reaction outlined above. Why?

CH3

O

H

CH2

O

H

CH3

O

H

H2C

O

H

H

H

a

b

d

c

Products formed:Possible combinations

a

b d

c

CH3

CH3

H

OH3C

OH

H

CH2

O

H

H

CH3

HOH

CH3

O

H

CH2H

OHH

CH2

O

H

CH2H

OHH

Problem: write out a simple mechanism for the formation of (a), (b), (c) and (d)

Problem: write out the structures of the products that would be obtained if dehydration of (a), (b), (c) and (d) occurred. You should get more than 4 products. Why?

Synthetically useful Mixed Aldol Reactions

• Mixtures are formed in Mixed Aldol Reactions because both carbonyl compounds have α-hydrogens.

• Mixed Aldol Reactions can be controlled in a variety of ways. They are for example synthetically useful if only one of the two reactants has an α-hydrogen – this is the situation if one of the reactants is an aromatic aldehyde:

O

H

+

H3C CH3

O

NaOHHO

CH3

O

H CH3

O

H

H

NaOH

Problem: one other product could be formed in the Aldol Condensation Reaction involving these two molecules. What is it?

Problem: draw the structure of the Aldol Addition product that would be obtained from benzaldehyde and ethanal, and of the major product resulting from the corresponding Aldol Condensation Reaction.

Carboxylic Acids

Famous carboxylic acids

Ethanoic Acid(Acetic Acid)

Methanoic Acid (Formic Acid)

Benzoic Acid

H3C CO

OHH C

O

OH

C C

C

CC

C

H H

C

HH

HOH

O

O

OHH3C

CH3

HO CO2HH

Hexanoic Acid (Caproic Acid)

(S)-(+)- Lactic Acid

HO2C CO2HHO CO2H

Citric Acid

R CO

OH

General Formula Functional Group

Nomenclature of carboxylic acids• Name ending: oic acid

• The carbon of the acid FG is always given the number 1

• All the usual rules apply

H3COH

H3C

O

Problem:

(a) Name the following acid: (b) Draw the structure of the following acid: 2,3-dimethylpentanoic acid

Physical Properties

very polar-possibility of

hydrogen bondingC,H non-polar

• BP is high because of strong intermolecular forces

• Water solubilityR small or medium: complete water solubility (like dissolves like)R large: lower water solubility

• In non-polar solvents: carboxylic acids form dimers (two unit systems)

R CO

O H

δ

δ δ

δ

H3C CO

OCH3C

O

O

H

Hδ δ

δδ

Preparation of carboxylic acids

Special case: acetic acid (ethanoic acid)

CO

OHH3CC

O

HH3C

O2C CH

H

H

Hcatalyst

O2

catalyst

CO

OHH3C

O2

catalystH3CCH2CH2CH3

CO

OHH3C

catalystH3COH + CO

All reactions occur in the gas phase (high T and P)

and involve heterogeneous catalysts

World demand is 6.5 million tonnes / year: 1.5 million tonnes come from recycling and most of the rest from petrochemical feedstocks (as above). Used in producing polymers, pharmaceuticals, dyes, agrichemicals, etc.

General methods: redox reactions (see Preparation of Alcohols above)

Chemical Reactions

1. Carboxylic acids are acidic!(a) In water they ionize to give H+ ions (protons), the active ingredients of acids

CO

OHH3C C

O

OH3C + H+

They are weak acids as dissociation / proton donation is partial

Why are they acid at all? The carboxylate anion is stabilized by resonance and so is happy to form.

Resonance hybrid: actual structure of the anion - very stable as the charge is not

carried by a single atom

resonance forms C

O

OH3C C

O

OH3C C

O

OH3C≡

(b) Any other factor which reduces the electron density in the carboxylateanion, makes it easier for it to form and so increases the acidity of the acid

eg the presence of an electronegative (EN) atom such as F

The inductive effect of the F atom draws some of the

electron density away from the carboxylate ion stabilizing it further and thus increasing

the acidity of the acid

Increasing the number of EN atoms further increases the acidity:

COH

OH2C C

O

OH2C

F F

<

<

COH

OH3C C

OH

OXH2C C

OH

OX2HC C

OH

OX3C< < <

Carboxylic acids undergo the standard reactions of acids

(a) Reaction with metals

CO

OH3CC

O

OHH3C + Na

Na+ 1/2 H2 ↑

(b) Reactions with bases

Compare with

Compare with

HCl + Na Na Cl + 1/2 H2

CO

OCH+ KOH

K+ H2O

H3C

H3CC

O

OHCH

H3C

H3C

HCl + KOH K Cl + 1/2 H2O

2. Redox reactionsCarboxylic acids can be reduced to aldehydes (see Preparation of Alcohols above) .

3. Conversion to carboxylic acid derivatives

R C

O

OH

R

O

OR1

R

O

Cl

R

O

NH2

R

O O O

R

P2O5(-H2O)

R1OH, H+

SOCl2

R1NH2

NaOHH2O

H+, H2O

H2O

H2O

anhydride

ester

acyl chloride or acid chloride

amide

A carboxylic acid derivative can be

made from the parent acid and converted to

it by reaction with water (hydrolysis)

Reactivity: acyl chloride > anhydride > ester > amide

R C

O

OH

R

O

OR1

R

O

Cl

R

O

NH2

R

O O O

R

P2O5(-H2O)

R1OH, H+

SOCl2

R1NH2

R C

O

OH

R

O

OR1

R

O

Cl

R

O

NH2

R

O O O

R

P2O5(-H2O)

R1OH, H+

SOCl2

R1NH2

R C

O

OH

R

O

OR1

R

O

Cl

R

O

NH2

R

O O O

R

P2O5(-H2O)

R1OH, H+

SOCl2

R1NH2

R

O acyl group

The formation of a carboxylic acid derivative– a detailed look: esterification of a carboxylic acid

H2SO4+ H2OH3C

O

OH

+ H3CCH2OH H3C

O

OCH2CH3

δ+

δ−

• One of the problems with using this type of reaction to make esters is that its equilibrium constant is close to 1 and so at equilibrium only about 50% of the starting materials have been converted to product

• If we are trying to make an ester with a simple alcohol (eg methanol, ethanol, etc.), we can make use of the Principle of Le Chatelier to force the reaction to go to completion. If use a large excess of alcohol the reaction will move to the right-hand side to try to remove it and in so doing will convert almost all of the carboxylic acid to the ester. The excess alcohol is easily removed afterwards as its boiling point will be lower than that of the product • This won’t work if the alcohol is expensive or if it is difficult to remove after the reaction.

H3C

O

OH

δ+

δ−H

CH2CH3

O

H

H3C

OH

OH

H3C

OH

HO

OCH2CH3

H

H3C

O

HO

OCH2CH3

H

+ H2OH3C

O

OCH2CH3

+ H

H

Ester formation: the mechanism

The catalyst converts the δ+ into a whole +, making the carbon more electrophilic and more attractive to the nucleophilic alcohol

The catalyst is regenerated

tetrahedral intermediate

A second example of the conversion of a carboxylic acid into a carboxylic acid derivative: acyl chloride formation

H3C

O

O

H

ClS

O

Cl

H3C

O

O

H

S

O

ClCl

H3C

O

OS

O

Cl

H

H3C

O

OS

O

Cl

+ Cl

Cl

δ+

δ+

δ−

δ−

H3C

O

OS

O

ClCl

+ HH3C

O

Cl + SO2 + Cl

acyl chloride

thionylchloride

good leaving group

a gas: leaves the reaction mxture as

it is formed

tetrahedral intermediate

tetrahedral intermediate

Nucleophilic Acyl Substitution

This term describes the reactions of carboxylic acids and their derivatives that we have been considering above:

R

O

X

Y

δ+

δ−

R Y

O X

R

O

Y+ X

tetrahedral intermediate

R

Oacyl group

Examples

Acid → ester : OH substituted by OR

Acyl chloride → amide: Cl substituted by NH2

Acid → acyl chloride: OH substituted by Cl

All these reactions involve the substitution

of the group X attached to the acyl

group by a nucleophilic group Y

Key points in relation to nucleophilic acyl substitution

• If X- is not a good leaving group then Y- leaves again and we are right back where we started.

• HO- is not a good leaving group and so carboxylic acids are relatively unreactive in terms of nucleophilic acyl substitution

• In the conversion of the acid to the acyl halide using SOCl2, the success of the reaction is based on replacing the OH with OS(O)Cl which is a much better leaving group. The acid is said to be activated towards nucleophilic acyl substitution by this replacement.

• The fact that Cl- is a good leaving group accounts for the reactivity of acyl chlorides in terms of nucleophilic acyl substitution

Activation of carboxylic acids for nucleophilic acyl substitution in biosynthesis

• Biosynthesis is the process of making molecules in biological systems – for example, in a cell

• The carboxylic acid group is a common component in biological molecules which thus can use nucleophilic acyl substitution as a building tool

• The problem is that activated carboxylic acids – such as acyl chlorides would not survive in the aqueous environment in which biosynthesis takes place

• Nature activates carboxylic acids in a different way - by converting them into acyl phosphates or acyl pyrophosphates

Use of acyl phosphates and acyl pyrophosphates in biosynthesis

R OP

O

O O

O

P

O

OO

R OP

O

O O

O

acyl phosphates acyl pyrophosphates

R OP

O

O O

OY

δ+

δ−

+R O

PO

O O

OYR

O

Y OP

O

O

O

≡ PO43-

Using these activated carboxylic acids in nucleophilic acyl substitution

phosphate ion

R OP

O

O O

OR O

PO

O O

O

good leaving groups

Recommended Text

Organic Chemistry (5th Ed.),

Paula Y. Bruice

Pearson Education/Prentice Hall

Library: 547 BRU