Reactions in Organic Compounds HOMO LUMO reaction Energy ...
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Transcript of Reactions in Organic Compounds HOMO LUMO reaction Energy ...
Reactions in Organic Compounds
HOMO
LUMO
reaction
Energy gain
product nucleophile
electrophile
As we first learned with acid/base reactions with Lewis definition, any reaction can be considered as a nucleophile reacting with an electrophile
All reactions thus involve a filled molecular orbital (called HOMO, representing the nucleophile) reacting with an empty molecular orbital
(called LUMO, representing the electrophile)
electrophile nucleophile
product
The closer in energy the HOMO is to the LUMO means there
will be a greater energy gain
Studying an Organic Reaction
How do we know if a reaction can occur?
And – if a reaction can occur what do we know about the reaction?
Information we want to know:
How much heat is generated?
How fast is the reaction?
Are any intermediates generated?
(What is the THERMODYNAMICS of the reaction?)
(What is the KINETICS of the reaction?)
(What is the reaction mechanism?)
CH3ONa CH3Cl CH3OCH3 NaCl
All of this information is included in an Energy Diagram
Potential energy
Reaction Coordinate
Potential energy
Reaction Coordinate
Possible Mechanism 1 Possible Mechanism 2
Starting material
Starting material Products
Products
Transition states
Transition states
Intermediate
If we know the “shape” of the reaction coordinate, then all questions about the mechanism can be answered (thermodynamics and kinetics)
Equilibrium Constants
Equilibrium constants (Keq) indicate thermodynamically whether the reaction is
favored in the forward or reverse direction and the magnitude of this preference
Keq = ([C][D]) / ([A][B]) = ([products]) /([starting material])
ΔG
Reaction Coordinate
A B C D
Gibb’s Free Energy
The Keq is used to determine the Gibb’s free energy
ΔG = (free energy of products) – (free energy of starting materials)
If we use standard free energy then ΔG˚ (25˚C and 1 atm)
Keq = e(-ΔG˚/RT)
or
ΔG˚ = -RT(ln Keq) = -2.303 RT(log10 Keq)
A favored reaction thus has a negative value of ΔG˚ (energy is released)
Contributions to Free Energy
ΔG˚ = ΔH˚ -TΔS˚
The free energy term has two contributions: enthalpy and entropy
Enthalpy (ΔH˚): heat of a reaction (due to bond strength) Exothermic reaction: heat is given off by the reaction (-ΔG˚)
Endothermic reaction: heat is consumed by the reaction (+ΔG˚)
Entropy (ΔS˚): a measure of the freedom of motion - Reactions (and nature) always prefer more freedom of motion
Organic reactions are usually controlled by the enthalpy
Bond Dissociation Energies
The free energy of organic reactions is often controlled by the enthalpic term
- The enthalpic term in organic reactions is often controlled by the energy of the bonds being formed minus the energy of the bonds being broken
The energies of bonds is called the Bond Dissociation Energy
Many types of bonds have been recorded (both experimentally and computationally) we can therefore predict the equilibrium of a reaction by knowing these BDE’s
Kinetics
A second important feature is the RATE of a reaction
The rate is not determined by Keq, But instead by the energy of activation
(Ea)
Knowing the Ea of a reaction tells us how fast a reaction will occur
Ea
Reaction Coordinate
Rate therefore depends on the structure of the transition state along the rate determining step
ΔG
While both the thermodynamics and kinetics depend on the structure of the starting material, the thermodynamics depends on product structure
while rate depends on transition state structure
Rate Equation
The rate of a reaction can be written in an equation that relates the rate to the concentration of various reactants
Rate = kr [A]a[B]b
The exponents are determined by the number of species involved for the reaction step - The exponents also indicate the “order” of the reaction with respect to A and B
Overall order of the reaction is a summation of the order for each individual reactant
A B C D
Relationship between Rate and Energy of Activation
Referring back to our energy diagram the rate can be related to the energy of activation (Ea)
kr = Ae(-Ea/RT)
A is the Arrhenius “preexponential” factor
Ea is the minimum kinetic energy required to cause the reaction to proceed
As a general guide, the rate of a reaction generally will double every ~10˚C increase in temperature
(as the temperature of a reaction increases, there are more molecules with the minimum energy required to cause a reaction to occur)
Reactivity with Substituted Alkyl Halides
Substituted alkyl halides will undergo reactions not seen with alkanes
Consider electron density distribution
Thus the halogen substitution has made the carbon more “electrophilic”
Chlorine causes a bond dipole
Chloromethane Ethane
This dipole results in electron density being distributed
toward chlorine and away from carbon
Reactivity with Substituted Alkyl Halides
The alkyl halide is “electrophilic” due to the relative placement of the LUMO orbital
Remember that we compare reactivity due to the relative placement of orbitals RELATIVE to the unreactive C-C bonds
C (sp3) C (sp3)
σ C-C
σ* C-C
C-C single bonds are relatively unreactive due to large overlap of sp3 hybridized
orbital and energy match, therefore very low HOMO and high LUMO energy
σ C-Cl
σ* C-Cl
C (sp3)
In a C-Cl bond, an sp3 orbital from carbon is still being mixed so same energy level It is mixed, however, with a p orbital on chlorine which is much lower in energy
(more electronegative)
Cl (p)
Poor energy match means orbitals do not mix as much, therefore LUMO is very low
Also why nucleophile reacts at carbon in LUMO
And why C-Cl bond is broken
(node in C-Cl bond)
Low energy LUMO makes alkyl halides reactive toward nucleophiles (compounds with a high energy HOMO orbital)
When Cl leaves and nucleophile attacks (concerted or sequentially) determines the type of reaction
This process does not occur with alkanes (carbon-carbon bonds are difficult to break)
There are many problems with this type of reaction (bond is not polarized therefore carbon is not electrophilic, poor leaving group, breaking a strong bond, etc.),
but mainly due to high energy of the LUMO for an alkane bond
CH3O Na H3C Cl CH3OCH3 NaCl
CH3O Na H3C CH3
Reactivity with Substituted Alkyl Halides
Type of Reactions that can Occur with Alkyl Halides
Substitutions: a halide ion is replaced by another atom or ion during the reaction
Therefore the halide ion has been substituted with another species
Eliminations: a halide ion leaves with another atom or ion -no other species is added to the structure
Therefore something has been eliminated
One Type of Substitution, SN2
Substitution – Nucleophilic – Bimolecular (2)
One substituent is substituted by another
Both the original starting material and the nucleophile (which becomes part of the product) are involved in the transition state for the rate determining step
Therefore this is a bimolecular reaction
Potential Energy Diagram for SN2
Reaction Coordinate
CH3O H3C Cl
H
HH
H3CO Cl
CH3OCH3 Cl
Bond is forming Bond is breaking
H
HH
Transition state in a SN2 reaction resembles a sp2 hybridized carbon
NUC LG
Species in a Given SN2 Reaction
nucleophile electrophile transition state products
Electron rich nucleophile reacts with electron poor electrophile
A SN2 reaction is dependent upon the characteristics of the nucleophile and substrate (electrophile)
HO ClH
HH
H
HHHO Cl CH3OH Cl
Kinetics
A SN2 reaction is a second order reaction
First order in respect to both the nucleophile and the electrophile
Rate = k [CH3Cl][HO-]
Both methyl chloride and hydroxide are involved in the transition state so they both are involved in the rate equation
*characteristic for all SN2 reactions, second order overall and first order in both substrate and nucleophile
Stereochemistry of SN2 Reaction
As the electrophilic carbon undergoes a hybridization change during the course of the reaction the substituents change in this view from pointing to the left in the starting material
to pointing to the right in the product
This is referred to as an “inversion of configuration” at the electrophilic carbon
Therefore the stereochemistry changes (three-dimensional arrangement in space)
*another characteristic of SN2 reactions, all SN2 undergo an inversion of configuration
HO ClH3C
HD
CH3
HDHO Cl HO
CH3
HDCl
Chiral sp3 hybridized carbon
Chiral sp3 hybridized carbon
Achiral sp2 hybridized carbon
Consequence of Inversion in a SN2 Reaction
A chiral carbon is still chiral but the chirality is inverted (the R and S designation usually change
but this depends on the priority of the new substituents)
NUC LGH
HHNUC
H
HHLG
ClH3C
HDHO HO
CH3
HDCl
CH3
Cl D
CH3
D OH
R S
Rate of SN2 Reaction
As seen with rate equation, the characteristics of both the substrate and the nucleophile will affect the rate of a SN2 reaction
In any rate question, need to ask how the energy of the starting materials and transition state along the rate determining step are related
Never answer a rate question using the energy of the product, product energy affects thermodynamics not kinetics
Reaction Coordinate
Only this part of reaction coordinate affects the rate
Effect of Substrate
As the number of substituents on the electrophilic carbon increases the rate decreases
Methyl Fast SN2 rate
Primary Slower SN2 rate
Secondary SN2 rate slows
Tertiary No SN2 occurs
Sterics of substrate has dramatic effect on rate of SN2 reaction, methyl halides react fast but 3˚ halides do not react at all
C
H
HH
BrHO C
CH3
HH
BrHO C
CH3
CH3H
BrHO C
CH3
CH3H3C
BrHO
Consider Approach of Nucleophile
Nucleophile must be able to react with electrophilic carbon in a SN2 reaction
Nucleophile must be able to react with “blue” electrophilic carbon for reaction to proceed
Electrophilic carbon is artificially painted blue
Bromomethane Looking backside of C-Br
bond
Bromoethane tertbutylbromide
Br
H HH
As the length of a substituent chain increases the sterics do not increase dramatically
C
H
HH
BrHO C
CH3
HH
BrHO C
CH2
HH
BrHO
H3C
C
H2C
HH
BrHO
CH3
Effect of Substrate
Methyl Fast SN2 rate
Ethyl Slower SN2 rate
Propyl (CH3 trans to Br)
Severe sterics
Propyl (CH3 gauche to Br)
Similar to ethyl
As the bulkiness, or branching, of a substituent increases the rate does drop dramatically
Effect of Substrate
C
H2C
HH
BrHO
CH3
C
HC
HH
BrHO
CH3CH3
C
C
HH
BrHO
CH3CH3H3C
Propyl (CH3 gauche to Br)
Similar to any primary
2-methylpropyl Increased sterics
slower rate
2,2-dimethylpropyl (adjacent to quaternary) Severe sterics, no rate
*SN2 reactions do not occur on carbon adjacent to quaternary carbon
Effect of Nucleophile
The nucleophile will also have an effect on the rate of a SN2 reaction
product
In a SN2 reaction, the HOMO of the nucleophile reacts with the LUMO of the electrophile
The closer in energy these two orbitals are located, the greater energy stabilization is obtained during the reaction
electrophile
nucleophile
product
stabilization stabilization
In a typical SN2 reaction, the nucleophile is a negative charged species and the electrophile is a carbon 2p orbital
CH3O Na H3C Cl CH3OCH3 NaCl
H
HHCH3O
The closer in energy the nucleophile is to the carbon 2p orbital thus is more reactive and the nucleophile is called more “nucleophilic” (the nucleophilicity increases)
Factors in Nucleophile Characteristics
Strength of nucleophile
A strong nucleophile has a high density of electrons available to form a new bond
Electron density plots
A deprotonated form (base) is thus always more nucleophilic than the conjugate
H2O HO-
This also means the HOMO is higher in energy in the deprotonated form
Factors in Nucleophile Characteristics The placement of the HOMO indicates how reactive the nucleophile will be in a SN2
C (sp3) C (sp3)
σ C-C
σ* C-C
C-C single bonds are relatively unreactive due to large overlap of sp3 hybridized
orbital and energy match, therefore very low HOMO and high LUMO energy
CH3- NH2- HO- NH3 H2O
In the HOMO of CH3 anion, the electron pair is in an unmixed sp3 orbital, the negative charge
raises the energy relative to radical, thus have a very high HOMO (very reactive)
Amide (NH2-) also is in an unmixed sp3 orbital, but due to higher nuclear charge, nitrogen anion
is lower in energy than carbon anion
Hydroxide is even lower in energy than amide due to greater nuclear charge for oxygen
The neutral NH3 and H2O are lower in energy than the deprotonated form
All of these HOMOs are much higher in energy than the mixed C-C σ bond
General Trends in Nucleophilicity
- A species with a negative charge is a stronger nucleophile than a similar species without a negative charge. In other words, a base is a stronger nucleophile than its conjugate acid
- Nucleophilicity decreases from left to right along a row in the periodic table. Follows same trend as electronegativity (the more electronegative atom has a higher affinity for electrons
and thus is less reactive towards forming a bond)
- Nucleophilicity increases down a column of the periodic table, following the increase in polarizability
All of these trends assume a nucleophile reacting with a carbon based electrophile in polar/protic solvents
Solvent is typically the most abundant species present in a reaction, and the type of solvent used plays a tremendous role in causing the trends outlined
A more electronegative atom also means the HOMO of the atom is more stable, therefore the energy gap with the LUMO of the electrophile is greater and thus less
stabilization
Solvent Effects on Nucleophilicity
Solvation impedes nucleophilicity
In solution, solvent molecules surround the nucleophile the solvent molecules impede the nucleophile from attacking the electrophilic carbon
smaller anions are more tightly solvated than larger anions in protic solvents
IF H-Bonding
Any solvent with acidic hydrogens are protic solvents (usually involves O-H or N-H bonds)
Alcohols (methanol, ethanol, etc.) and amines are therefore protic solvents
To increase nucleophilicity of anions a solvent is necessary that does not impede the nucleophile (thus does not solvate the charged species)
Use polar/aprotic solvents (have dipole with no O-H or N-H bonds)
Solvent Effects on Nucleophilicity
H3C C NH3C
O
CH3 H
O
NCH3
CH3
Acetonitrile Acetone Dimethylformamide (DMF)
Sterics of Nucleophile
As the site of negative charge in the nucleophile becomes more sterically hindered the reaction becomes slower (higher energy of activation)
ethoxide anion tert-butoxide anion
Remember the Rate of a SN2 Reaction is Related to the Transition State Structure
The higher the energy of this transitions state structure, the higher the energy of activation
Sterics of Nucleophile
As the nucleophile becomes more bulky, the energy of the transition state structure will increase and thus the rate of reaction will be slower
C
H
HH
BrHOBrH
HHHO HO
H
HHBr
Effect of Leaving Group
For a SN2 reaction to proceed not only is a strong nucleophile required but there must also be a good leaving group
Requirements: Electron withdrawing
(polarizes C-X bond to make carbon more electrophilic)
Needs to be stable after gaining two electrons (therefore not a strong base)
As polarizability increases, rate increases (stabilizes the transition state)
The stability of the leaving group is manifest in the energy diagram
- If it is unstable the energy of the products will be high therefore the reaction will become endothermic and
the equilibrium will favor the starting materials
- In the transition state the leaving group is only partially bonded therefore if the energy of the leaving group is high the energy of the transition state will also be high
and thus the rate will be slower
Effect of Leaving Group
Good leaving groups are WEAK bases
Therefore the conjugate base of a strong acid can be a good leaving group
A leaving group obtains excess electron density after the reaction
Ability to handle the excess electron density determines the leaving group stability
CH3O H3C Cl CH3OCH3 Cl
Conjugate of HCl
HO RO NH2 Should never be used as leaving groups
These are strong nucleophiles, but very poor leaving groups
Most Strong Nucleophiles are Poor Leaving Groups
Since strong nucleophiles have a high electron density at the reacting site this makes them poor leaving groups, which need to spread out the excess
electron density over the molecule
There are notable exceptions - Primarily the halides
I-, Br-, Cl- are good leaving groups and are also nucleophilic
Fluoride is the Exception
F- is a very poor leaving group - Should never have F- leave in a SN2 reaction
Due to poor polarizability of fluoride
Same reason why fluoride is a worse nucleophile than the other halogens, the leaving group needs to be polarizable to lower the energy of the transition state
Modifying the Leaving Group
Good leaving groups are WEAK bases, but how can STRONG bases be made into good leaving groups?
CH3O H3C OH H3CO CH3 OH
Very poor leaving group
If want OH group to leave, need to modify group so leaving group is a WEAK base
One of the simplest ways to do this conversion is to run a reaction in acidic media, the alcohol would thus be protonated first to create H2O as a leaving group rather than hydroxide
H3C OH H Br H3C OH2Br Br CH3 H2O
Good leaving group
Ethers are relatively unreactive -main reason that they are common solvents for organic reactions
One of the few reactions that they can undergo is alkyl cleavage with HI or HBr which converts the -OR substituent (a poor leaving group) into an alcohol (a good leaving group)
Similar to converting an hydroxy group (poor leaving group) into H2O (good leaving group)
OH+
OH
BrOH Br+
HBr
Br
Modifying the Leaving Group
HI > HBr >>> HCl
Using common abbreviations:
Modifying the Leaving Group
Another method to convert an alcohol into a good leaving group is to form tosylates
SH3CO
OCl
OH
N
OTsCl
N H(TsCl)
OH TsCl
pyridine
OTs
Tosylates as Leaving Groups
The tosylate is commonly used as a way to convert the alcohol group into a good leaving group
The tosylate anion is more stable than a hydroxide anion due to resonance
NUCOTs
H
HHNUC
H
HHOTs
CH3
SO OO
CH3
SO OO
CH3
SO OO
Alkyl halides can thus be prepared from alcohols with phosphorous halides
An example with PBr3:
SN2 reaction – works well for 1˚ and 2˚ alcohols, bulkier alcohols do not go through SN2 reaction
Modifying the Leaving Group
Another way to modify the alcohol group into a good leaving group is to react with phosphorous reagents
Phosphorous is very “oxophilic” and thus forms strong bonds with oxygen
H3C OH Br2P BrH3C O
PBr2Br Br CH3
Effect of Solvent
In addition to the effect on leaving group ability, the solvent can affect the rate of a SN2 reaction due to stabilization of points along the reaction coordinate
In order to answer any rate question, consider the energy of activation due to the difference in energy between starting material and transition state
Reaction Coordinate
Need to consider structures for a particular reaction
(CH3)3N Br N(CH3)3 Br
(CH3)3N Br
HH
BrN!+ !- Lower in energy
with increasing solvent polarity
Small effect on stability with increasing solvent polarity
Rate will increase with increasing solvent polarity
Another Type of Substitution, SN1
Reaction Coordinate
While a SN2 reaction will occur with a good rate with methyl and 1˚ carbons, the reaction does not occur at 3˚ carbons
The reason is due to the high energy of activation caused by the sterics of a nucleophile reacting with inversion of configuration at a 3˚ site
1˚ carbon
3˚ carbon
If t-Butyl iodide is reacted with methanol, however, a substitution product is obtained
This product does NOT proceed through a SN2 reaction
First proof is that the rate for the reaction does not depend on methanol concentration (not a second order reaction)
Occurs through a SN1 reaction
Another Type of Substitution
Second proof is when the 3˚ carbon is chiral, reaction does not proceed with inversion (reaction is not stereospecific)
BrH3C
H3CH3C
CH3OH OCH3H3C
H3CH3C HBr
Substitution – Nucleophilic – Unimolecular (1) SN1
- In a SN1 reaction the leaving group departs BEFORE a nucleophile attacks
For t-butyl bromide this generates a planar 3˚ carbocation
The carbocation can then react with solvent (or nucleophile) to generate the product in a second step
CH3OH
If solvent reacts (like the methanol as shown) the reaction is called a “solvolysis”
BrH3C
H3CH3C CH3
H3CH3C
Br OCH3H3C
H3CH3C
The Energy Diagram for a SN1 Reaction therefore has an Intermediate
- And is a two step reaction
Potential energy
Reaction Coordinate
Br
CH3H3CH3C
CH3H3CH3C
OCH3
CH3H3CH3C
Rate Characteristics
The rate for a SN1 reaction is a first order reaction
Rate = k [substrate]
The first step is the rate determining step
The nucleophile is NOT involved in the rate determining step
Therefore the rate of a SN1 reaction is independent of nucleophile concentration (or nucleophile characteristics, e.g. strength)
Stereochemistry of SN1 Reaction
- Due to planar intermediate in SN1 reaction, the reaction is NOT stereospecific
CH3OH
R
S
Enantiomers (if equal then racemic) CH2CH2CH3
H3CH3CH2C
OCH3
CH2CH2CH3H3CH2CH3C
OCH3
CH2CH2CH3H3CH2CH3C
Often obtain racemic mixtures with SN1 reaction
- Sometimes there is a higher fraction of inversion than retention
This is due to the leaving group “blocking” approach for retention configuration
CH3OH
CH3OH
Hindered approach
Unhindered approach
Stereochemistry of SN1 Reaction
Don’t forget the leaving group
Br
CH2CH2CH3H3CH2CH3C CH2CH2CH3
H3CH3CH2C
Br
This is a dramatic difference between SN2 and SN1 reactions
SN2 reactions always give inversion of configuration at the reacting carbon (therefore stereospecific reactions)
SN1 reactions are not stereospecific
- With no steric interference of the leaving group obtain a racemic mixture - With steric interference of the leaving group obtain a preference for inversion
compared to retention but still obtain both stereoisomers
Stereochemistry of SN1 Reaction
What is Important for a SN1 Reaction?
The primary factor concerning the rate of a SN1 reaction is the stability of the carbocation formed
If this structure is made more stable then the rate will be faster
Effect of Substrate
CH3H3CH3C
Remember that a carbocation is an ELECTRON DEFICIENT structure
Factors that stabilize electron deficient structures
- Number of alkyl substituents at carbocation site (due to hyperconjugation)
3˚ 2˚ 1˚
CH3H3CH3C
HH3CH3C
HH3CH
Effect of Substrate
- Another way to stabilize an electron deficient center is through resonance
Effect of Substrate
Effect of Leaving Group
Leaving group ability
Same factors as already seen in SN2 reactions
Want polarizable group Need a leaving group that departs as a weak base
Faster SN1 rate due to better leaving group
CH3OHI
CH3H3CH3C
CH3OHCl
CH3H3CH3C
Effect of Solvent
In a typical SN1 reaction, the starting material is neutral and the transition state has partial charges developing and the intermediate has a formal positive charge
Remember that anything that can stabilize the transition state relative to the starting material will cause a lower Ea and a faster rate
Therefore when the solvent is more polar the transition state will be stabilized
BrH3C
H3CH3C CH3
H3CH3C
BrH3C
H3CH3C
!-!+
Solvent with higher polarity will therefore increase the rate of a typical SN1 reaction
For the solvolysis of t-butyl chloride the rate in different solvents:
Effect of Solvent
OO
H3C
O
CH3H3C OH
Diethyl ether Tetrahydrofuran Acetone Methanol
Dielectric constant 4.3 7.6 21 32.7
Relative rate 1 55 690 4.3 x 106
As the solvent polarity increases, the rate of SN1 reaction increases dramatically
Comparison with SN2 reaction
Compare the reaction coordinate for a SN1 reaction with a SN2 reaction
In a typical SN2 reaction, a negatively charged nucleophile reacts with a neutral starting material to generate a transition state with partial charges
Both the starting materials and the transition state are negatively charged (can change depending on what nucleophile and substrate are used)
HO BrH
HH
HBrHO
HH
!- !-
Comparison of SN2 versus SN1 Reactions
Effect of Nucleophile
- SN2 is a one step reaction where both the substrate and nucleophile are involved
- SN1 is a two step reaction involving the initial formation of a planar carbocation
Therefore:
SN2 strong nucleophiles are required
SN1 nucleophile strength does not affect rate
Effect of Substrate
Two important considerations: -as the number of substituents on the carbon increase the stability
of a formed carbocation increases (therefore of lower energy) For a SN1 reaction 3˚ halides are the best
-as the number of substituents increase, the bulkiness at the electrophilic carbon increases
For a SN2 reaction methyl halides are the best
SN1 substrate: 3˚ > 2˚ (1˚ and methyl halide do not react)
SN2 substrate: methyl halide > 1˚ > 2˚ (3˚ does not react)
Effect of Leaving Group
-in both reactions the bond between the electrophilic carbon and the leaving group breaks in the rate determining step
Therefore both SN1 and SN2 reactions required a good leaving group
Weak bases that are common leaving groups:
Cl Br I H3C SO
OO
Halides Sulfonates
Effect of Solvent
In a typical SN1 reaction a neutral starting material is ionized to charged intermediates in the rate determining step
In a typical SN2 reaction the charge is kept constant during the rate determining step (charge changes places, but the total amount of charge is the same)
SN1 good ionizing solvent favored SN2 solvent has less of an effect
*Need to compare structures for starting material and transition state for rate determining step, if the amount of charge changes the effect of solvent on reaction rate will change
Using Substitution Reactions in Synthesis
Substitution reactions are used extensively to synthesize more complex molecules from simpler (meaning cheaper!) starting materials
Part of the creativity of organic synthesis is that a given starting material can be converted to a variety of different functional groups
Only using SN2 reactions, for example, a wide selection of functional groups can be created
Br OHNaOH
By knowing which mechanism is operating, it is possible to predict not only the structure of the product (depending upon the electrophile and nucleophile used)
but also the stereochemistry and how the rate would change with changes in concentration of reagents used or the solvent used for the reaction
To make alcohols more nucleophilic, need to abstract the acidic hydrogen (remember pKa’s!)
With this method, can make nucleophilic oxygen that can react through any SN2 type reaction already studied
Using Oxygen Nucleophiles
Cannot react with 3˚ alkyl halides, however, as SN2 reaction will not occur
Will obtain elimination product instead
OH O ONaH CH3Br
Williamson ether synthesis
O
CH3
CH3
BrH3C
H3CH3C
Using Sulfur Nucleophiles
Due to the more polarizable sulfur, and bigger atom which results in less solvation in protic solvents, the thiolate is more nucleophilic than an oxygen anion
This increased nucleophilicity allows the formation of sulfonium salts
Same reaction does not occur readily with ethers
SH S SHO Br
SCH3Br
S
Sulfonium salts are used as alkylating agents
Similar to SN2 reactions observed with methyl halides
SNUC NUC CH3 S
trimethylsulfonium
NUCCH3Br NUC CH3
Sulfur Electrophiles
These sulfonium salts are used as methylating agents biologically
Methyl halides cannot be used in living cells –low water solubility and too reactive (will react nonselectively with amines)
Common methylating agent in living cells is S-Adenosyl methionine (SAM)
S-Adenosylmethionine (SAM)
S-Adenosylhomocysteine (SAH)
N
NN
NNH2
O
OHOH
SCH3O
ONH3
NUC
N
NN
NNH2
O
OHOH
SO
ONH3
NUC CH3
Sulfur Electrophiles
S-Adenosylmethionine (SAM) S-Adenosylhomocysteine (SAH)
One example: Conversion of norepinephrine to epinephrine
Sulfur Electrophiles
N
NN
NNH2
O
OHOH
SCH3O
ONH3
HO
HOOH
NH2
Norepinephrine (noradrenaline)
N
NN
NNH2
O
OHOH
SO
ONH3
HO
HOOH
NHCH3
Epinephrine (adrenaline)
Using Acetylide Nucleophiles
The terminal sp hybridized C-H bond in an alkyne is far more acidic (pKa ~ 25) than either a sp2 hybridized C-H in an alkene (pKa ~ 44) or a sp3 hybridized C-H in an alkane (pKa ~ 60)
The lower acidity allows the terminal hydrogen to be abstracted easier with common bases
R HNH2
RH3C Br
R CH3
Often use amide bases
The acetylide anion can then be reacted in a SN2 reaction with an alkyl halide
Allows the synthesis of a wide variety of alkynes starting with acetylene
This SN2 reaction only works well with methyl or 1˚ alkyl halides
Using Nitrogen Nucleophiles
The lone pair of electrons on amines can react in a nucleophilic manner
NH2 CH3I NH
Yield is best with methyl or primary halide (this is a SN2 reaction)
One problem with this reaction is often polyalkylation occurs
CH3I NNH
Will continue until quaternary amine is obtained
Using Nitrogen Nucleophiles
To prevent “over alkylation” reaction is run with excess of amine
NH2 CH3I NH
10 equivalents
The other option is to run the reaction with excess of alkyl halide
In that case the product will be the quaternary salt where the amine has been fully alkylated