CH221 CLASS 19
CHAPTER 11: REACTIONS OF ALKYL HALIDES – NUCLEOPHILIC SUBSTITUTIONS AND ELIMINATIONS
Synopsis. Class 19 begins considering the substitution and elimination reactions of alkyl halides by discussing the SN2 mechanism and the factors that influence it. At the end, there is a short discussion of substitution reactions in synthesis.
Introduction
Because of the electrophilic nature of the halogen-containing carbon atom and the corresponding slightly acidic nature of the hydrogen atoms on the adjacent carbon (the “-hydrogens”), the reactions of alkyl halides are dominated by nucleophilic substitution (SN) and elimination (E):
Indeed, nucleophilic substitutions and eliminations are two of the most important reaction types in organic chemistry, where X is not necessarily (though it is frequently) halogen.
It was discovered, by Paul Walden in the late 19th century, that certain reactions occur with inversion of configuration at the reaction site. This is now called the “Walden inversion”. Some years later, Kenyon and Phillips demonstrated that certain substitution reactions occur with inversion of configuration, but it wasn’t until the 1930s that Hughes and Ingold showed that complete inversion of configuration accompanies all bimolecular nucleophilic substitutions, which were now called SN2 reactions. The work (described above) of all these pioneers was with primary or secondary alkyl halides or their equivalents, such as tosylates (see later).
The SN2 Reaction
Many primary and secondary alkyl halides react with strong nucleophiles (see later) in substitution reactions that involve just one step, in which the new bond is made and the old one is broken in a synchronous manner:
The kinetic rate law for such a reaction is
Rate = k[CH3Br][OH-]
Or, more generally, rate = k[RX][Nu-]
The term SN2 was first used by Hughes and Ingold: it stands for bimolecular nucleophilic substitution.
The chief features of the SN2 reaction are summarized below for the displacement of bromide from 2-bromobutane by hydroxide to give 2-butanol.
Any factor that increases G at a particular temperature will lead to a slower SN2 reaction at that temperature. This includes factors that lower the reactant energy (such as effective solvation of the nucleophilic reagent) and those that increase the transition state energy (such as steric hindrance or unfavorable electronic interactions). In a similar way, any factor that decreases G will result in a faster SN2 reaction
Characteristics of SN2 Reactions
As implied above, some SN2 reactions occur readily (i.e. they are fast), whereas others occur only slowly, or not at all. It is now time to examine the factors that influence the rates of SN2 reactions.
These factors are inherent in the nature of the substrate structure, the nucleophile, the leaving group and the solvent.
Influence of the Substrate: Electronic and Steric Effects
It has long been known that in the reaction
R-Br + Cl- R-Cl + Br-,
Methyl bromide reacts most readily, followed by bromoethane, 1-bromopropane (and other primary halides) and then various simple secondary alkyl halides. The following is a reactivity sequence:
Substrate (CH3)3CBr (CH3)3CCH2Br (CH3)2CHBr CH3CH2Br CH3Br
3o hindered 1o 2o 1o methyl
(neopentyl)
Rel. rate <1 1 500 4 x 104 2 x 106
SN2 reactions are NOT favored by branched substrates: the best substrates are methyl halides, primary halides and some simple secondary halides
The effect of branching can be explained by a combination of electronic and steric effects:
The lack of reactivity of vinyl and aryl halides can be explained in a similar manner:
Similarly, the lack of SN2 reactivity at bridgehead carbon atoms can be explained by a high-energy transition state, this time arising partly from steric hindrance and partly by the inability of the reaction carbon to invert its configuration, because of ring strain:
1-chloronorbornane
The above examples all illustrate ways in which certain structural features can destabilize the transition state, that is to say, increase its energy (with respect to the reactant ground state energy), thereby increasing G, so that the rate of reaction is decreased. Other structural aspects can stabilize the transition state, thereby making the SN2 reaction more favorable. This can occur particularly when there are favorable electronic interactions in the transition state, such as when there is an unsaturated group conjugated with the reaction site. Consider the data below for the following reaction, in acetone:
R-Cl + I- R-I + Cl-
R CH3CH2 CH2=CH-CH2 PhCH2 PhCOCH2
Rel. rate 1 33 93 105
The transition state in the last case above is strongly stabilized by delocalization, via p- orbital overlap:
Influence of the Nucleophile
Under a given set of conditions, different nucleophiles have different reactivities (nucleophilic strengths or “nucleophilicities”), resulting in different SN2 reaction rates. For example, examine the data for the following reaction in aqueous ethanol:
CH3-Br + Nu- CH3-Nu + Br-
Nucleophile H2O CH3COO- Cl- Br- OH- I- CN- SH-
Rel. rate 1 500 103 8x103 16x103 11x104 12.5x104
It is evident from the above data that the best nucleophiles are generally those with the following characteristics.
- The presence of a negative charge: anions are the best nucleophiles.
- Basic strength. When comparing nucleophiles that have the same reacting atom (e.g. oxygen), those that are the stronger bases are generally the better nucleophiles, e.g. OH- is better than CH3COO-, which in turn, is better than H2O.
- Size: larger simple anions are better nucleophiles than smaller ones, e.g. I- is better than Br- , which in turn, is better than Cl-. This is mainly because of higher polarizability and lower solvation requirements of larger anions.
small anion - high solvation large anion – low solvation
Influence of the Leaving Group
The better the leaving group, the faster the SN2 reaction. The best leaving groups (X) are those that are best able to stabilize a negative charge: those that are the weakest bases and, consequently, those that are derived from the strongest acids (HX). The following general scale of reactivities is applicable to most SN2 reactions.
Leaving group X CN- OH- NH2- OR- F- Cl- Br- I- TosO-*
Rel. reactivity <1 1 200 104 3x104 6x104
It can be seen that the poor leaving groups are CN-, OH-, NH2-, OR- and F-. This means that nitriles, alcohols, amines, ethers and alkyl fluorides do not normally undergo SN2 reactions. However, it is possible to convert some of these poor leaving groups into good leaving groups by simple chemical reactions. For example, the hydroxyl group of alcohols can be “activated” in acidic solution or (better) by reaction with tosyl chloride (p-toluenesulfonyl chloride):
See later for examples of activation of hydroxyl groups using PBr3.
Influence of the Solvent
The rates of SN2 reactions are affected by the solvent in different ways, depending much upon the nature of the nucleophile and the leaving group, but we will consider here only the displacement of one anionic group by another.
Consider the data below for the reaction
CH3CH2CH2CH2-Br + N3- CH3CH2CH2CH2N3 + Br-
Solvent CH3OH H2O DMSO DMF CH3CN HMPA
Rel. rate 1 7 1300 2800 5000 2x105
It can be seen from the data that polar protic solvents, like water and methanol are the poorest, whereas the best are that are called polar aprotic solvents (DMSO to HMPA, above). This is because polar protic solvents readily solvate anionic nucleophiles, thereby stabilizing them and lowering their ground state energies, as shown below.
Polar aprotic solvents, on the other hand, although they dissolve salts (from whence anionic nucleophiles are derived), they solvate cations only, leaving the anions almost free of solvation and hence with higher ground state energies:
It can be seen overleaf that the structures of polar aprotic solvents can readily interact with cations, but not with anions.
Summary of SN2 Characteristics
Substrate. Branching raises the energy of the transition state, increases G and decreases the rate of reaction. The best substrates are methyl and primary alkyl.
Nucleophile. More reactive nucleophiles are less stable, have higher ground state energies, thereby decreasing G and increasing the reaction rate. The best nucleophiles are large basic anions.
Leaving group. Good leaving groups (more stable anions) lower the energy of the transition state, decreasing G and increasing the reaction rate.
Solvent. Protic solvents solvate the nucleophile, lower its ground state energy, which increases G and decreases the rate of reaction. Polar aprotic solvents do not solvate the nucleophilic anion, leaving it with a higher ground state energy, decreasing G and increasing the reaction rate.
Nucleophilic Substitution Reactions and Synthesis
Nucleophilic substitutions are important reactions in organic chemistry – they occupy prominent positions in many organic syntheses. Indeed, we have seen a number of examples already, but it will be useful to examine the following two examples again.
These examples will now serve both to illustrate a problem associated with SN reactions, arising from competitive elimination (E) reactions and to introduce the difference between SN2 and SN1 reactions. Accordingly, the same two examples also give a short preview of the topics of the final two classes, SN1 reactions and elimination reactions.
In example 1, note that the alkyl halide used is primary: good yields of substitution product are obtained in this case. However, if the halide is secondary or tertiary, elimination competes successfully with substitution, especially as this nucleophile is also a very strong base.
In the second example, tertiary alcohols react rapidly with HBr because the substitution mechanism is not SN2 but SN1, which involves the generation of a carbocation intermediate – 3o cations are more stable than 2o or 1o cations:
On the other hand, 1o and 2o alcohols react readily with PBr3 because this reagent converts the poor leaving group OH into a very good one:
Class Questions
- What product would you expect from an SN2 reaction of (R)-1- bromo-1-phenylethane with cyanide ion (-CN)?
- Which substance of the following pairs is more reactive as a nucleophile?
(a) (CH3)2N- or (CH3)2NH (b) (CH3)3B or (CH3)3N (c) H2O or H2S
(a) (CH3)2N- (b) (CH3)3N (c) H2S
- Rank the following compounds in order of their expected reactivity toward the SN2 reaction:
CH3Br, CH3OTos, (CH3)3CCl, (CH3)2CHCl
CH3OTos > CH3Br >(CH3)2CHCl > (CH3)3CCl