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


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


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


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


HI > HBr >>> HCl

Using common abbreviations:


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


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)


- 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


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


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


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)


-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


S-Adenosylmethionine (SAM) S-Adenosylhomocysteine (SAH)

One example: Conversion of norepinephrine to epinephrine


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

reactions in organic compounds homo lumo reaction energy

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