Substitution Reactions of Alkyl Halides H3CH2C H3C H3C H3C C H3C :N(CH3)3 H C Cl CH3S- Na+ CH3CN H3CS H C CH2CH3

CH3 H3C H3C C H3C Br Br + NaCl

HBr, OH

Br

+ H2O

H3CH2C

H3CH2C

N(CH3)3

OSO2CH3

NaI, acetone I + NaOSO2CH3

SN1 reactions in which the solvent participates as a nucleophile are called solvolysis reactions. involve displacement of a heteroatom from carbon -- the "leaving group" the leaving group is always more EN than carbon making the carbon electrophilic the carbon is always sp3 hybridized there is always a nucleophile present, either -ve or d -

Important Synthetic Reactions that are Substitutions Many important functional groups can be prepared by using Substitution reactions. Examples involving C-C bond formation: CH3CH2Br + NaCN CH3I + H3C C C CH2 CH3CH2CN H3C C C CH3 Nucleophile Result

PhCH2Cl +

O2N

PhCH2CH2NO2

Examples involving C-O bond formation: CH3CH2CH2CH2Cl + HO CH3I + PhO (CH3)3CBr (CH3)3CBr CH3OPh + H2O + HOCH3 (CH3)3COH (CH3)3COCH3 CH3CH2CH2CH2OH

Examples involving C-S bond formation: CH3CH2Br + NaSH CH3I + CH3CH2CH2S CH3CH2SH CH3CH2CH2SCH3

Examples involving C-N bond formation:

CH3CH2CH2CH2Cl + H3N

CH3CH2CH2CH2NH3

PhCH2Cl + Br

N(CH3)3

PhCH2N(CH3)3 Cl

N3 + NaN3

CH3CH2CH2CH2Cl + KNCO

CH3CH2CH2CH2NCO

Examples involving C-H bond formation: CH3(CH2)8CH2Cl + LiAlH4 CH3(CH2)8CH3

Examples involving C - halogen bond formation: CH2Br + NaI CH2I

What makes a good nucleophile? It is hard to derive an accurate order of nucleophilic strength because, among other things, solvent plays an important role in SN2 reactions. Having said that, the following trends are a useful guide. Strong bases are good nucleophiles... so: A nucleophile with a negative charge is always a more powerful nucleophile than its conjugate acid. So, HO- is more nucleophilic than H2O, and H2N- is more nucleophilic than H3N:. For the same atom with the same charge, nucleophilicity parallels basicity: CH3CH2O > HO > PhO > CH3CO2 > H2O pKa conj. acid: For atoms in the second row of the periodic table, and with the same charge, nucleophilicity parallels basicity: H3C > H2N > HO > F Overall: R3C- > H2N- > RO- > HO- > R2NH > AcO- > ArO- > H3N: > F- > H2O. Going down the periodic table, nucleophilicity increases, though basicity decreases. Therefore, for halides: I- > Br- > Cl- > FGroup VIA: RSe - > RS - > RO Group VA: R3P > R3N

Steric bulk around the basic atom suppresses nucleophilicity... Diisopropylamide (LDA) H2N > N

H3C CH3CH2O > H C C O 3 H3C t-butoxide

Alkyl halides and alcohols undergo substitution by two mechanisms: SN1 and SN2.

The SN1 reaction involves a the formation of a carbocation reaction intermediate in rate determining step. SN2 involves the collision of the nucleophile with the carbon that bears the leaving group. 3, benzylic and allylic substrates undergo SN1 reactions because they form relatively stable carbocations. 1 substrates undergo SN2 reaction because they are sterically uncluttered at the reaction site. 2 substrates undergo both reaction types but slowly. To determine which, if either, mechanism is operating, you must learn to...

H CH3CH2CH2OH CH3CH2CH2Cl H3CH2C

Br CH3

H3C H3C C

CH3 OH

CH2Cl

CH2OH H C H C H H CH2Br H

H3C C C

CH3 C OH H

H3C

CH3 C OH CH2CH2Cl Br H C H C H Br

The SN1 Reaction H3C H3C C Br H2O H3C H3C C OH + HBr

H3C

H3C

SN1 reactions in which the solvent participates as a nucleophile are called solvolysis reactions. The Mechanism...

Br
H3C H3C C H3C Br H3C C H3C CH3

H3C H3C C H3C

H O H
Br

O H H

H3C H3C C H3C

O H H Br

H O H3C C

CH3 CH3 CH3 O H H H3C CH3

O H Br H O CH3 H3C O

H3C

O H

The reaction profile...

This mechanism operates when: the substrate forms a relatively stable carbocation the nucleophile is a weak base, preferably a neutral molecule like H2O, ROH etc. the reaction is done in a polar, protic (OH)solvent (water, alcohols, acetic acid etc.)

Factors that stabilize carbocations. Since the SN1 reaction involves the formation of carbocations in the rate determining step, only those species that form relatively stable carbocations will undergo this reaction in a timely fashion. H2 C Cl

H C H

H2C C H

Br

H3C

H2 C O Cl

Alkyl carbocations are stabilized by electron donation from adjacent C-H bonds, something that is known as hyperconjugation.

1 H

H H C H C H H H 3 H C H C C H So for alkyl carbocations, the order of stability is... H C H HH

Vinyl and aryl carbocations cannot be stabilized by resonance... H H

H or by hyperconjugation.

H C H C H

So, the order of stability of carbocations is:

Usually, SN1 reactions are practical for benzylic, allylic and 3 substrates.

The Hammond Postulate - a useful and oft used tool to rationalize the relative rates of analogous reactions. "The structure of a transition state tends to resemble that species to which it is closer in energy." For endothermic reactions... For exothermic reactions...

the transition state is closer in energy to the products and therefore said to be "productlike" in structure. From this, we infer something about the energy of the transition state from the stability of the product.

the transition state is closer in energy to the reactants and therefore said to be "reactantlike" in structure. From this, we infer something about the energy of the transition state from the stability of the reactants.

Nu: H3C H3C C H3C Br H3C H3C C Br CH3 H H3C H3C C H3C Nu H3C C H3C Br

Nu: C CH3 H3C H Br H H3C C H3C Nu

Therefore, when comparing reactions that involve the formation of carbocation intermediates in the RDS, the one involving the more stable carbocation intermediate will be formed ...

Reactions Involving Carbocations Br H3C C H3C H CH3 H3C C C H Elimination (E1 - the last step is a Brnsted acid/base reaction.) CH3 H3C C H3C CH3 H2C C CH3 H3C C H3C Addition H3C C H3C CH3 H C CH3 CH3 H3C C CH3 CH CH3 Rearrangement CH3 CH3 C CH3 H H O H H3C CH3 C C H H H3C CH3 H3C C Br Substitution (SN1 - the last step is a Lewis acid/base reaction).

H3C

H2 C

Carbocation rearrangements are often promoted by the presence of Lewis acids. In this case, the intermediates are said to be "carbocation-like" if not actual carbocations.
H H3C C CH3 AlCl3

CH2 Cl

H C CH3

CH2 Cl AlCl3

H3C

C CH3

CH3 AlCl4

H3C

Carbocation rearrangements are always possible when group migration can lead to a more stable carbocation. Generally this is an unwanted complication. H3C C H3C CH3 C CH3 I H

H2O/ CH3OH,

H3C C H3C CH3 CH3 C C H C

CH3 OH H

H3C C H3C OH C

CH3 H CH3 CH3 H CH3

H3C C H3C CH3 C

CH3 I H

H3C H3C

H3C C H3C C

CH3

H3C C H3C CH3 C

CH3 OH H

H3C C H3C OH C

CH3 H CH3

Another case... H Cl H2O/ CH3OH, H H

Yet another case... CH3 C CH3 CH3 H3C H3C C Cl H3C H3C C CH2Cl

CH3 C CH3 CH3

H3C AlCl3

H AlCl3

Stereochemistry of the SN1 Reaction Br C H3C NaI/Acetone CH2CH3 Ph H3C C CH2CH3 Ph

I C H3C CH2CH3 Ph H3CH2C Ph

I C CH3

Reactions in which the configuration of an asymmetric center is scrambled are said to occur with...

Sometimes (depending on conditions) reactions occur with only partial racemization. BrNaI/Acetone CH2CH3 Ph H3C C CH2CH3 Ph

Br C H3C

I C H3C CH2CH3 Ph H3CH2C Ph

I C CH3

The SN2 reaction Best for 1 and methyl substrates. I H3C Br

CH3

Br

The mechanism consists of a single elementary process.

The Stereochemistry of the SN2 reaction The reaction geometry is such that the collision must occur with the nucleophile attacking the back side of the CLG bond.

H3C

Br

CH3

Br

When attack occurs at an asymmetric carbon, the reaction occurs exclusively with inversion of the absolute stereochemistry. This is an example of a stereospecific reaction. H3C H3CH2C C H

Br

H3C

CH3 CH2CH3 C H

Br

Why backside attack? H C H Br H3C S H C H

H H3C S

H Br

Substrate structure and the rate of SN2 Substrate CH3Br CH3CH2Br CH3CH2CH2Br H3C C H3C H3C C H3C So the substrate structure dependence on rate is... CH3 Br H Br 0.015 H3C 0.004 H C CH3 H3C H3C C CH3 H2 C Br H2 C Br 0.052 Relative rate 100 1.31 0.81

More data... CH3Br CH3CH2Br CH3CH2CH2Br CH3CH2CH2CH2Br 100 1.31 0.81 0.52

0.00001

Neopentyl substrates are prone to rearrangement. H2O/ CH3OH, OTs H3C H3C C OH H3C C H3C C H2 CH3 H2 C CH3

H3C H3C C CH3

H2 C

The effect of solvent on the rate of SN1 and SN2 reactions... SN1 processes are fastest in polar, protic solvents due to ion-dipole stabilization of the developing charge in the transition state. Polar protic solvents...

Acetic Acid AcOH O C H3C OH

t-Butanol (t-BuOH) OH

Isopropanol (iPrOH) OH

Ethanol (EtOH) CH3CH2OH

Methanol (MeOH) CH3OH

Water H2O

Polar aprotic solvents are best for SN2 because the nucleophile is not as solvated. O C H3C Acetone O S H3C CH3 Dimethyl sulfoxide (DMSO) O H3CH2C CH2CH3 N Pyridine (Pyr) Tetrahydrofuran (THF) CH3 H3C C N CH3OCH2CH2OCH3 Dimethoxyethane (DME) H O C N(CH3)2

Acetonitrile (MeCN)

Dimethylformamide (DMF) O

Ethyl ether (Et2O)

Preparation of Amines vis SN2 OK for the preparation of 3 amines from 2 amines... OH NH Cl and quaternary ammonium compounds... CH3 CH3I CH3 N CH3 CH3 I N OH 70%

N CH3

But pitfalls in the synthesis of 1 or 2 amines... H3N: CH3CH2Br

CH3CH2NH3Br

CH3CH2NH3Br

H3N:

CH3CH2NH2

NH4Br

Wtih 16 eq. NH3 34% 1 57% 2 1% 3

CH3CH2NH2

CH3CH2Br

CH3CH2NH2CH2CH3

Br

Comparing SN2 and SN1 No. Steps Reaction order Substrate structure dependence

SN2 1 2nd

SN1 2 or 3 1st

CH3, 1 best. 2 OK but slow. Watch for b-branching. 3, vinyl, aryl do not react. None Stereospecific Inversion

Allylic, benzylic > 3. 2 very slow. 1, vinyl, aryl do not react. Carbocation. Racemization or partial racemization

Intermediate Stereochemical consequences

Solvent Competing reaction

Polar, aprotic. E2

Polar protic E1, E2, rearrangement.

Importance of nucleophile on rate

Very important. NR for weak nucleophiles like H2O, ROH.

Unimportant.

Substrate classification Methyl, CH3X

Weak base/ good Nu SN2 SN2

Moderate/strong base/good Nu SN2 SN2

Weak base/ weak Nu NR SN1

SN2 and SN1

E2 E2

SN1 SN1

SN1

1 Benzylic 2 Benzylic 3 Benzylic

SN2 and SN1 SN1 SN1

SN2 E2 E2

SN1 SN1 SN1

1 Allylic 2 Allylic 3 Allylic

SN2 and SN1 SN1 SN1

SN2 E2 E2

SN1 SN1 SN1

Aryl Alkenyl (Vinyl)

NR NR

NR NR

NR NR