Nucleophilic Substitution

Y : – RX Y R + : X – Nucleophile is a Lewis base (electron-pair donor), often negatively charged and used as Na + or K + salt. Substrate is usually an alkyl halide. Nucleophilic Substitution +

Halogens connected to sp 2 carbons are not reactive under the conditions discussed in this chapter. Effect of Hybridization of the Carbon sp 2 carbons not reactive sp 3 carbon reactive

Therefore, substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 12. Nucleophilic Substitution

+ RX Alkoxide ion as the nucleophile.. O:O: R' – Table 8.1 Examples of Nucleophilic Substitution gives an ether + : XR.. O R' –

(CH 3 ) 2 CHCH 2 ONa + CH 3 CH 2 Br Isobutyl alcohol (CH 3 ) 2 CHCH 2 OCH 2 CH 3 + NaBr Ethyl isobutyl ether (66%) Example

+ RX Carboxylate ion as the nucleophile.. O:O: R'C – O.. gives an ester + : X: XR.. O R'C – O Table 8.1 Examples of Nucleophilic Substitution

OKOK + CH 3 (CH 2 ) 16 C CH 3 CH 2 I acetone, water O + KIKI O CH 2 CH 3 CH 3 (CH 2 ) 16 C Ethyl octadecanoate (95%) O Example

+ RX Hydrogen sulfide ion as the nucleophile S:S: –.. H gives a thiol + : X: XR.. S H – Table 8.1 Examples of Nucleophilic Substitution

KSH + CH 3 CH(CH 2 ) 6 CH 3 Br ethanol, water + KBr 2-Nonanethiol (74%) CH 3 CH(CH 2 ) 6 CH 3 SHSH Example

+ RX Cyanide ion as the nucleophile – C N :: Table 8.1 Examples of Nucleophilic Substitution gives a nitrile + : X: XR – C N :

DMSO Br NaCN+ Cyclopentyl cyanide (70%) CN + NaBr Example

Azide ion as the nucleophile.. – N N N : : – + + RX Table 8.1 Examples of Nucleophilic Substitution.. gives an alkyl azide + : XR –.. N N N : – +

NaN 3 + CH 3 CH 2 CH 2 CH 2 CH 2 I 2-Propanol-water CH 3 CH 2 CH 2 CH 2 CH 2 N 3 + NaI Pentyl azide (52%) Example

+ RX Iodide ion as the nucleophile –.. : I : Table 8.1 Examples of Nucleophilic Substitution gives an alkyl iodide + : X: XR –.. I :

NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone. acetone +NaI CH 3 CHCH 3 Br 63% +NaBr CH 3 CHCH 3 I Example

Alkyl iodides are most reactive since: (a) the carbon-iodine bond is weakest for the halogens; (b) iodide is the weakest base of the halides (this implies that iodide is most stable) since HI is the strongest acid. Relative Reactivity of Halide Leaving Group

Since the rate of reaction depends on the halide the rate determining step must involve breaking of the carbon- halogen bond. S N 2 Mechanism of Nucleophilic Substitution Kinetic studies of the above reaction showed that the rate is also dependent on the hydroxide concentration: The rate determining step therefore involves both the nucleophile and the alkyl halide.

S N 2 Mechanism of Nucleophilic Substitution Overall reaction. The mechanism (one step). The transition state. The configuration at carbon. From

Potential Energy Diagram for S N 2 Reaction

The nucleophile attacks carbon from the side opposite the bond to the leaving group. The S N 2 reaction at a chirality center proceeds with inversion of configuration at the carbon bearing the leaving group. Inversion of Stereochemistry with S N 2

The reaction of (S)-2-bromooctane proceeds with inversion of configuration as shown in the equation: Inversion of Configuration The transition state is:

Steric Effects and S N 2 Reaction Rates

The rate of the reaction: RBr + Li I  R I + LiBr Effect of the Alkyl Group on the Rate decreases with increasing steric hindrance.The reaction is fastest with the least hindered methylbromide. The rate of S N 2 reactions normally decreases in the order: CH 3 X > primary > secondary > tertiary

Substitution on the  -carbon also slows reaction by adding steric hindrance to the carbon bearing the halogen. Effect of  -Substitution on the Rate Neopentyl bromide (a primary alkyl halide) is so hindered that it is essentially unreactive.

Nucleophiles and Nucleophilicity

Not all nucleophiles are negatively charged. Amines (R 3 N), sulfides (R 2 S) and phosphines (R 3 P) are good neutral nucleophiles. Neutral Nucleophiles

Solvolysis reactions with water (hydrolysis) and alcohols also involve neutral nucleophiles Neutral Nucleophiles S N 2 hydrolysis reaction mechanism:

Nucleophilicity (nucleophile strength) is a measure of how fast a Lewis base displaces a halogen in a reaction. The table compares rates of reaction with CH 3 I in CH 3 OH. Nucleophilic Strength

When comparing nucleophiles with the same nucleophilic atom then the stronger base is the stronger nucleophile. Nucleophilicity The stronger base is the conjugate base of the weaker acid. This generalization holds when comparing nucleophiles in the same row of the Periodic table

When comparing nucleophiles that have the same nucleophilic atom the charged nucleophile is stronger. Nucleophilic Strength

When comparing nucleophiles in the same group of the Periodic Table the most important factor is solvation of the nucleophile. Iodide is the weakest base of the halogens but the best nucleophile. The smaller chloride is a stronger base but is more solvated because it has higher charge density. Nucleophilic Strength

The S N 1 Mechanism of Nucleophilic Substitution

Tertiary alkyl halides are very unreactive in substitutions that proceed by the S N 2 mechanism. Do they undergo nucleophilic substitution at all? Yes. But by a mechanism different from S N 2. The most common examples are seen in solvolysis reactions. A question...

The reaction (CH 3 ) 3 CBr + 2 H 2 O  (CH 3 ) 3 COH + H 3 O + + Br - Nucleophilic Substitution of Tertiary Alkyl halides follows a first order rate law: Rate = k[(CH 3 ) 3 CBr] And the reaction is termed S N 1.

S N 1 Mechanism of Nucleophilic Substitution Step 1: Ionization to form a tertiary cation. Step 2: Addition of a water molecule. Step 3: Deprotonation.

Potential Energy Graph of the S N 1 Reaction

first order kinetics: rate = k[RX] unimolecular rate-determining step carbocation intermediate rate follows carbocation stability rearrangements sometimes observed reaction is not stereospecific much racemization in reactions of optically active alkyl halides Characteristics of the S N 1 mechanism

Comparison of a series of alkyl bromides under S N 1 reaction conditions (solvolysis) reveals that tertiary alkyl halides react fastest. The Alkyl Halide and the Rate of S N 1 Reaction In general, methyl and primary alkyl halides never react by the S N 1 mechanism and tertiary alkyl halides never react by S N 2.

S N 1 reactions proceed through the carbocation which is planar. Stereochemistry of the S N 1 Reaction The nucleophile can react from either side however, surprisingly a 1:1 mixture of products is not always formed.

The incomplete loss of stereochemistry is explained by a partial shielding of one side of the cation by the halide leaving group. Stereochemistry of the S N 1 Reaction

Rearrangements are evidence for carbocation intermediates and serve to confirm the S N 1 reaction mechanism. Carbocation Rearrangements in S N 1 Reactions

Mechanism with Rearrangement Step 2: H-shift (to form a more stable tertiary cation). Step 1: Ionization. Step 3: Water addition to the carbocation. Step 4: Deprotonation.

Solvent affects the rate of a reaction not the products formed and the questions are: 1. What properties of the solvent influence the rate most? 2. How does the rate-determining step of the mechanism respond to the properties of the solvent? Effect of Solvent on Substitution

Protic solvents are those that are capable of hydrogen bonding. Normally they have an –OH group or an N-H group. Aprotic solvents are not hydrogen bond donors. Polarity of a solvent is related to its dielectric constant (  ). Solvents with high dielectric constants are considered polar and those with low dielectric constants are non polar. Classification of Solvents

Properties of Solvents

Polar protic solvents hydrogen bond to, and solvate, the nucleophile and suppress its nucleophilicity and reduce the rate of reaction. Solvents and S N 2 Reactions Polar aprotic solvents cannot solvate the nucleophile and the nucleophile is free to react.

The table below shows the effect of solvent on this reaction. Solvents and S N 2 Reactions The reaction is much faster in polar aprotic solvents.

This reaction was studied under two different conditions. Solvents and S N 2 Reactions Reaction of hexyl bromide in a polar protic solvent required heating for 24 hours to form 76% of hexyl cyanide. With a polar aprotic solvent dimethyl sulfoxide and the less reactive hexyl chloride at room temperature for 20 minutes yielded 91 % of hexyl cyanide.

Comparison of the rates of solvolysis of (CH 3 ) 3 CCl and dielectric constant of the solvent shows faster reaction with more polar protic solvent. Solvents and S N 1 Reactions The reaction is much faster in more polar protic solvents.

The transition state for formation of the carbocation and the halide anion is lowered in a more polar solvent. Solvents and S N 1 Reactions

When... Primary alkyl halides undergo nucleophilic substitution: they always react by the S N 2 mechanism. Tertiary alkyl halides undergo nucleophilic substitution: they always react by the S N 1 mechanism. Secondary alkyl halides undergo nucleophilic substitution: they react by the S N 1 mechanism in the presence of a weak nucleophile (solvolysis). S N 2 mechanism in the presence of a good nucleophile.

Substitution and Elimination as Competing Reactions

Substitution and/or Elimination Lewis bases can react as nucleophiles or bases resulting in substitution or elimination.

Examples where both substitution and elimination products are formed: Substitution and/or Elimination The competition between substitution and elimination is:

The balance between substitution and elimination can be affected by changing from an unhindered base to a more hindered base. Unhindered base (CH 3 CH 2 ONa): predominantly substitution. Hindered base (CH 3 ) 3 COK: predominantly elimination Steric Effect on the S N 2/E2 Reactions

Nucleophiles that are weak bases tend to give higher ratios of substitution. Azide (N 3 - ) and cyanide (CN - ) are weak bases. Basicity and Substitution

Tertiary alkyl halides are very hindered and yield mixtures of substitution and elimination by S N 1 and E1 mechanisms with neutral nucleophiles. Nucleophiles and Tertiary Alkyl Halides Addition of stronger bases results in elimination exclusively through an E2 reaction.

Nucleophilic Substitution of Alkyl Sulfonates

Sulfonic acids are very strong acids similar to sulfuric acid. Nucleophilic Substitution of Sulfonates Alkyl sulfonates (ROTs) are prepared by reaction of alcohols with a sulfonyl chloride:

Sulfonates are stable anions and very weak bases because they are the conjugate bases of very strong acids. Nucleophilic Substitution of Sulfonates Sulfonates are therefore excellent leaving groups. Hydroxide (HO - ) is a very poor leaving group so transforming an alcohol into a sulfonate generates a good leaving group.

Alkyl sulfonates react faster than iodides. Nucleophilic Substitution of Sulfonates

Sulfonates are better leaving groups than halides so they can be used to form alkyl halides by substitution. Nucleophilic Substitution of Sulfonates

The formation of a tosylate does not change the configuration of the alcohol so an optically pure alcohol is transformed into an enantiopure tosylate. Nucleophilic Substitution of Sulfonates

Secondary tosylates undergo substitution with weak bases. Nucleophilic Substitution of Sulfonates Secondary tosylates also undergo elimination with strong bases.

Nucleophilic Substitution and Retrosynthetic Analysis

Retrosynthetic analysis works back from the target molecule. Here nucleophilic substitution reaction can form the thiol. Retrosynthetic Analysis Leaving group X could be a tosylate made from an alcohol. The alcohol could be made from an alkene.

Once the retrosynthetic analysis has been developed simply write the synthesis starting from the alkene. Retrosynthetic Analysis to Synthesis The full retrosynthetic analysis is: Anti-Markovnikov addition of H-OH