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Home , Substitution reaction

Substitution Reactions

Substitution reactions are reactions in which a displaces an or group of (the ) from a tetrahedral carbon atom.

Consider the following general substitution reaction:

Nu + R LG R Nu + LG

How might this reaction proceed?

We can imagine three different mechanisms:

•the nucleophile Nu-R bond forms first then the R-LG bond breaks. • the Nu-R bond forms at the same time as the R-LG bond breaks. •the R-LG bond breaks first then the Nu-R bond forms.

Are all these mechanisms reasonable? The two mechanisms that are operative in substitution reactions are the SN1 and SN2 reactions.

•Reactions in which the leaving group leaves before the attack of the

nucleophile are referred to as SN1 reactions. •Reactions in which the nucleophile attacks at the same time as the

leaving group leaves are referred to as SN2 reactions.

S stands for substitution N stands for nucleophilic The number refers to the number of reacting molecules in the rate determining step. In substitution reactions the RDS is the step where the leaving groups leaves.

Consider the two different mechanisms for a substitution reaction. What factors would favour one pathway over the other? Substitution Reactions of Halides

H H H CH C CH S- Na+ 3 2 3 CH2 CH3 C Cl H CS C + NaCl CH CN 3 H C 3 3 CH3

H3 C H C H C HBr, ² 3 3 H3 C C OH C Br + H2O H C 3 H3 C

:N(CH ) 3 3 Br H3 CH2 C Br H3 CH2 C N(CH3 ) 3

NaI, acetone OSO2 CH3 I + NaOSO2CH3

All of these reactions: • involve displacement of a heteroatom from carbon -- the "leaving group" • have a leaving group that is more EN than carbon making the carbon electrophilic • have an electrophilic carbon that is sp3 hybridized • have a nucleophile present, which is either -ve or -

Remember: Good leaving groups are weak bases! Alkyl halides and SN1 or SN2?

.3°, benzylic and allylic substrates undergo SN1 reactions because THEY FORM RELATIVELY STABLE .

.1°, substrates undergo SN2 reactions because they DO NOT FORM STABLE CARBOCATIONS and THE REACTION SITE IS STERICALLY ACCESSIBLE.

.2°, substrates can undergo both types of reaction, but do so slowly.

Th e SN1 Re actio n

H C H C 3 H O 3 H C 2 3 C Br H3 C C OH + HBr

H3 C H3 C

. SN1 reactions in which the participates as a nucleophile are called solvolysis reactions. Substitution Reactions – SN1

Sketch a reaction profile diagram for the following reaction:

I + (H3C)3C Br I C(CH3)3 + Br Substitution Reactions – SN1

SN1 reactions predominate when: •A relatively stable is formed. •The solvent is polar and protic.

•Weak nucleophile (e.g. a neutral molecule such as H2O, ROH, etc.).

Carbocation Stability

Carbocation stability is dependent on: •Coulombic stabilization •Inductive stabilization •Delocalization (resonance) •Hyperconjugation. Carbocation Stability – Resonance Delocalization

Since SN1 reactions involve carbocation intermediates, only those species that form reasonable carbocations will undergo this reaction is a timely fashion (this lifetime).

CH2 Cl

H H2C Br C C H H

H2 H3C C O Cl Carbocation Stability – Resonance Delocalization

. Aryl and vinyl carbocations cannot be stabilized by resonance. The empty orbital is orthogonal to the π-system and as such cannot be delocalized: . Alkyl carbocations are also stabilized by electron donation from adjacent C–H bonds.Alkyl ca Thisr b oca phenomenontion s a r e sta b i lisize knownd b y el easct r ohyperconjugationn d on a tion fr om a.d ja cen t C-H b on d s, som eth in g t h a t is kn own a s h yp er con ju ga t ion . 1 9 .5 ° H 1 ° 3 ° H H H C H C C C C H H H H H H C H H H . Recall that inductive and field arguments suggest carbocation stability is: 3° > 2° > 1° . Vinyl and aryl carbocations CANNOT be stabilized by resonance. Vin y l a n d a r y l ca r b o ca t io n s ca n n o t b e st a b ilize d b y r eso n a n ce... H 6 0 ° H H C C H H C C H H oorr b byy h hyperconjugation!y p er con ju gation . Thus, the order of carbonium ion stability is:

Benzylic ~ allylic > 3° > 2° > 1° > CH3 > vinyl ~ aryl

. Usually, SN1 reactions are practical for benzylic allylic and 3° substrates. SN1 - Rearrangements • One consequence of reactions proceeding via carbocation intermediates is the occurrence of rearrangement side reactions. Consider the following reaction:

• The substitution product is a constitutional isomer of the product expected. Propose a mechanism for the above reaction: SN1 - Rearrangements

It is worth noting that carbocation rearrangements can involve shifting either a hydride ion or a methyl anion. In either case, you will always be forming a more stable carbocation.

Pay close attention to the way curly arrows are drawn when proposing a hydride or methyl shift. We should be able to tell if you are proposing a hydride shift or generation of a pi bond. The SN1 Reaction - Kinetics.

- - I + (CH3)3CBr → (CH3)3CI + Br Consider:

- •What happens to the rate of production of (CH3)3CI if the concentration of I is held constant and the concentration of (CH3)3CBr is increased?

•What happens to the rate of production of (CH3)3CI if the concentration of - (CH3)3CBr is held constant and the concentration of I is increased? The of the SN1 reaction

Br NaI/Acetone CH2CH3 C H3C C CH2CH3 Ph H3C Ph

I CH CH H C 2 3 C 3 Ph CH2CH3 C H3C Ph I . The nature of the intermediate is such that the nucleophile can attack from either side with equal likelihood.

. Reactions in which the configuration of a chiral centre is scrambled are said to occur with . The Stereochemistry of the SN1 reaction

Sometimes (depending on conditions) reactions occur with only partial racemization.

Br- Br NaI/Acetone CH2CH3 C H3C C CH2CH3 Ph H3C Ph

I CH2CH3 C H3C CH CH Ph H C 2 3 C 3 Ph I

14 SN1 reactions –

. SN1 reactions are typically done in polar protic . Polar protic solvents are used because they help stabilize the transition state during the process of forming the carbocation intermediate. The more stabilized the transition state, the faster the carbocation will form.

Some common polar protic solvents:

O OH C OH CH3CH2OH CH3OH H2O H3C OH Acetic Acid t- AcOH Isopropanol Water (t-BuOH) (iPrOH) (EtOH) (MeOH) The SN2 Reaction.

The SN2 reaction is favoured for 1° and methyl substrates.

I H3C Br I CH3 Br

Sketch a reaction profile diagram for the above reaction. The SN2 Reaction - Kinetics.

I H3C Br I CH3 Br

Consider:

•What happens to the rate of production of CH3I if the concentration of CH3Br is held constant and the concentration of I- is increased?

- •What happens to the rate of production of CH3I if the concentration of I is held constant and the concentration of CH3Br is increased? 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 C—LG bond.

I + H3C Br I CH3 + Br

When attack occurs at an asymmetric carbon, the reaction occurs exclusively with inversion of the absolute stereochemistry.

H3C CH3 H3CH2C H3C CH2CH3 C Br CH3S + S C + Br H H

Stereospecific: A reaction in which the mechanism dictates that different steroisomeric reactants give different stereoisomeric products. The Stereochemistry of the SN2 reaction Why backside attack?

H H H H3C H C Br S C Br H3C S H H SN2 reactions - Reactivity Substrate dependance:

Substrate Relative rate Substrate Relative rate

CH3Br 100 CH3Br 100

CH3CH2Br 1.31 CH3CH2Br 1.31

CH3CH2CH2Br 0.81 CH3CH2CH2Br 0.81

H3C CH3CH2CH2CH2Br 0.52 H C 0.015 Br H H2 H3C H C 3 C 0.052 C Br H3C CH3 CH C 0.004 3 Br H3C H2 H3C H3C C C Br 0.00001

CH3 SN2 reactions – Solvent Effects

SN2 reactions are typically done in polar aprotic solvents. These solvents are polar enough to solubilize the nucleophile but do not stabilize the enough to prevent reaction.

Some common polar aprotic solvents:

O O

C H3C C N CH3OCH2CH2OCH3 C H3C CH3 H N(CH ) Acetonitrile Dimethoxyethane 3 2 Acetone (MeCN) (DME) Dimethylformamide (DMF) O O O S H3CH2C H3C CH3 CH2CH3 Dimethyl sulfoxide Ethyl ether N (DMSO) (Et2O) Pyridine Tetrahydrof uran (Pyr) (THF) SN2 reactions - Reactivity

When evaluating SN2 reactions, you have to consider everything involved in the reaction. This includes the substrate, the nucleophile, the leaving group and the solvent.

For each set of reactions, draw the SN2 products. Then indicate which reaction should proceed faster and why.

A

B SN2 reactions - Reactivity

For each set of reactions, draw the SN2 products. Then indicate which reaction should proceed faster and why.

C

SH + Br

SH Br SN1 vs. SN2 reactions – Comparison

SN2 SN1 Reaction Order second order reaction first order reaction

Minimum # Steps 1 or more steps 2 or more steps

Intermediates? No carbocation

Stereochemical stereospecific inversion of racemization (full or partial) Consequences configuration at electrophilic site at electrophilic site

Importance of very important; no reaction unimportant

Nucleophile Strength for weak nucleophiles like H2O Importance of very important; no reaction for very important; no reaction for Leaving Group weak leaving groups like HO- weak leaving groups like HO- Substrate Structure avoid steric hindrance; need carbocation stabilization;

Dependence CH3 > 1 > 2(slow) > 3 (no); 3 > 2 (slow) > 1 (no); no reaction for aryl/vinyl resonance stabilization helps; no reaction for aryl/vinyl

Solvent polar aprotic polar protic

Competing Reactions E2 E1, E2, rearrangement SN1 vs. SN2 reactions

. Would you expect the following reactions to proceed via SN1, SN2, both, or neither? Draw the expected product(s) for each reaction.

NaI acetone

Ag+