CHEM 331, Organic Chemistry I

A. The S_N2 Reaction.

Kinetics: Rate = k [RX] [Nu:-]. Both RX and Nu:- are involved in the rate-determining step.

Nucleophile: Negatively-charged (strong nucleophile) work best; occasionally neutral nucleophiles can be used. See examples at the end of Handout.

Reactivity of alkyl halides: CH₃ > 1° > 2° due to steric effects that hinder backside attack. 3° halides do not react. Allyl (CH₂=CH-CH₂X) and benzyl (C₆H₅CH₂X) halides are unusually reactive (comparable to or more reactive than methyl).

Stereochemistry: Complete inversion of configuration via pentacoordinate carbon Transition State.

Rearrangements: Do not occur

Solvents: Wide variety can be used, but polar, aprotic solvents (see end of Handout) are favored and usually cause 2° halides to react by this mechanism.

Transition State:

Kinetics: Rate = k [RX]. Only RX is involved in the rate-determining step.

Nucleophile: Neutral (weak nucleophile) work best; see examples at the end of Handout.

Reactivity of alkyl halides: 3° > 2° due to the relative stabilities of carbocations that form (electronic effects). Methyl and 1° halides do not react. Allyl and benzyl halides are unusually reactive due to the exceptional stabilities of the allyl and benzyl carbocations (resonance effects).

Stereochemistry: Partial racemization via intimate and solvent-separated ion pairs.

Rearrangements: Occur if a more stable carbocation can form.

Solvents: Wide variety can be used, but polar, protic solvents (see end of Handout) are favored and usually cause 2° halides to react by this mechanism.

Transition State:

Carbocations are involved in this mechanism, with some features of carbocations being:

Stability: 3° > 2°. The more stable an intermediate is, the more easily it is formed; hence the relative reactivities of and halides. Methyl and 1° carbocations are seldom formed. Allyl and benzyl carbocations form readily because of resonance stabilization of the positive charge.

Rearrangements: If possible, a carbocation may rearrange to a more stable one by an alkyl group shift or a hydride shift. The most common rearrangement is from a 2° to 3° ion. Primary carbocations, if formed (and they seldom are), could rearrange to either a 2° or 3° cation.

Example:

From a practical standpoint, S_N2 reactions are useful for introducing various functional groups in place of halogen in 1° and 2° halides. Only one substitution product is formed, and many different nucleophiles can be used. Optically active halides cleanly invert their stereochemistry in a S_N2 reaction.

S_N1 reactions are considerably less useful for several reasons. Only a limited number of nucleophiles may be used, possible carbocation rearrangement can lead to multiple products and racemization of the optically active substrates.

C. The E2 Reaction.

Kinetics: Rate = k [RX] [B:-]. Both RX and B:- are involved in the slow, rate-determining step.

The base: Strong bases, such as KOH/alcohol or NaOCH₂CH₃ (NaOEt), are required.

Reactivity of alkyl halides: 3° > 2° > 1°. With a strong base, alkyl halides undergo elimination by the E2 reaction.

Rearrangements: Do not occur

Solvents: Reaction can occur in a variety of solvents. The use of a strong base is the driving force for elimination to occur.

Reactants:

1) Must have one or more hydrogens.

2) H and the leaving group must be anti to one another and must be in the same plane as the two carbons to which they are attached.

Products: If two or more alkenes are produced, the one having the greater or greatest number of carbon-containing substituents attached to the C=C bond is usually the major product. The reason for this trend is based upon the stabilities of various alkenes, with the more or most stable alkene being formed more easily and thus is the major product.

Isotope Effects: Because breaking the C-H bond is involved in the rate-determining step, the use of D in place of H results in different rates of reaction because it is more difficult to break a C-D bond than a C-H bond. For example, CD₃CH₂Br undergoes E2 elimination more slowly than CH₃CH₂Br.

Transition State:

Kinetics: Rate = k [RX]. Only RX is involved in the slow, rate-determining step.

The base: Weakly basic substances, such as H₂O, CH₃OH, and CH₃CH₂OH can cause elimination to occur by the E1 reaction.

Reactivity of alkyl halides: 3° > 2°> 1° halides usually do not undergo E1 reaction. Note: If a strong base is present, E2 reaction occurs.

Rearrangements: If possible, a carbocation may rearrange to a more stable one by an alkyl group shift or a hydride shift. The most common rearrangement is from a 2° to 3° ion. Primary carbocations, if formed (and they seldom are), could rearrange to either a 2° or 3° cation.

Rearrangement occurs more rapidly than does the loss of a proton from a carbocation, so rearrangement products usually predominate.

Solvents: Reaction is favored in polar, protic solvents.

Reactants:

1) Must have one or more hydrogens.

2) Unlike the E2 reaction, no special geometry is required.

Products: If two or more alkenes are produced, the one having the greater or greatest number of carbon-containing substituents attached to the C=C bond is usually the major product. The reason for this trend is based upon the stabilities of various alkenes, with the more or most stable alkene being formed more easily and thus is the major product.

Isotope Effects: None. The rate-determining step doesn't involve breaking a C-H or a C-D bond. For example, (CH₃)₃CBr undergoes E1 elimination at the same rate as (CD₃)₃CBr.

Transition State:

From a practical standpoint, E2 reactions are useful for converting alkyl halides into alkenes, even when a mixture of alkenes is formed. E2 reactions can be carried out on any class of alkyl halide.

E1 reactions are considerably less useful for converting alkyl halides into alkenes. In addition to formation of the mixture of alkenes, more elimination products yet can be formed if a carbocation rearrangement is possible.

E. Competition Between S_N1 and E1 Reactions.

Unlike the S_N2 and E2 reactions that occur by different mechanisms, the S_N1 and E1 reactions have one thing in common: both involve the initial formation of a carbocation intermediate resulting from the solvent assisted ionization of the C-X bond. Once formed, the carbocation may undergo several type of reactions:

1. react with a nucleophile to give products

2. lose a proton from the -carbon(s) to give one or more alkenes

3. rearrange to a more stable carbocation that undergoes reactions 1) and 2)

In the examples that follow, pay particular attention to the class of alkyl halide and the solvent if specified. These features indicate if both substitution and elimination occur. You should be able to identify the type of mechanism (E1 or S_N1) and identify the major alkene formed in elimination.<

S_N2 and E2 reactions compete to give substitution and elimination. This competition exists when alkyl halide is 1° or 2°; with 3° halides, elimination is the only reaction of importance. Primary halides generally undergo substitution much more readily than elimination, unless the base is very strong and bulky.

Nucleophiles that are basic, such as OH-, result in competition. A limited number of nucleophiles, such as , are weakly basic (soft bases) and hence cause only substitution to occur without any elimination.

In the examples that follow, pay particular attention to the class of alkyl halide and the nature of the nucleophile (weak or strong base), and the solvent if specified. These features dictate the type of mechanism(s) and whether substitution and/or elimination occurs. You should write mechanisms for each example. You should be able to identify the type of mechanism (E2 or S_N2) and identify the major alkene formed in elimination.

To properly determine the correct or most plausible mechanism(s) for substitution and/or elimination, consider the following factors. This is precisely the analysis that was done in the examples given above.

1. Classify halide (1°, 2°, 3°) and identify the nucleophile. Is the latter negatively-charged or neutral? Is it a soft or a hard base?

2. Examine starting materials and, if given, products.

a) If the nucleophile is on a different carbon than the leaving group or if the carbon skeleton has changed, consider S_N1 and carbocations for substitution, and E1 for elimination.

b) If the nucleophile is on the same carbon as the leaving group and there is no change in the structure of the carbon skeleton, consider S_N2 and for substitution, and E2 for elimination.

3. Regarding the nucleophile/base:

a) If it is negatively charged and a hard base, consider S_N2 and for substitution, and E2 for elimination.

b) If it is negatively charged and a soft base, consider S_N2 (there will be no substitution if halide is 3° and no elimination unless the solvent is polar, protic). If it is neutral, consider S_N1 and E1.

4. Identify the class of alkyl halide.

a) If primary, consider S_N2 and/or E2.

b) If secondary, consider S_N2 or E2 (in aprotic solvent) or S_N1 or E1 (in polar, protic solvent).

c) If tertiary, consider S_N1 or E1 only.

5. 2° halides may react by some combination of S_N2, S_N1, E1 or E2. The mechanism is often dictated by the solvent. Aprotic polar solvents favor S_N2/E2 and polar, protic - S_N1/E1.

6. If a 2° carbocation is formed, always consider possible rearrangement to a more stable 3° carbocation (see Carbocations Section above).

1. Weak, charged nucleophiles (soft bases) (Favor S_N2).

OH^-, CN^-, I^-, RS^-

2. Weak, neutral nucleophiles (soft bases) (Favor S_N1 and E1)

ROH, H₂O, RSH, R₃P:

3. Strong nucleophiles (hard bases) (Favor S_N2 and E2)

Cl^-, RNH₂, RCO₂^- (mainly S_N2)

F^-, RO^-, HO^-/alcohol, NH₃, CO₃^2- (mainly E2)

1. Polar, protic solvents (good H-bonding donors and acceptors) (Favor S_N1 and E1).

ROH, H₂O, RNH₂, liq. NH₃, CH₃CO₂H

2. Polar, aprotic solvents (no H-bonding, but good dipoles) (Favor S_N2 and E2).

L. Ryzhkov

August, 1996