Bimolecular nucleophilic substitution

Nucleophilic substitution

In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of substitution reaction in which an "electron rich" nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom attached to a group or atom called the leaving group; the positive or partially positive atom is referred to as an electrophile.

The most general form for the reaction may be given as

Nuc: + R-LG → R-Nuc + LG:

The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged.

An example of nucleophilic substitution is the hydrolysis of an alkyl bromide, R-Br, under alkaline conditions, where the attacking nucleophile is the OH and the leaving group is Br-.

R-Br + OH → R-OH + Br

Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorised as taking place at an aliphatic (saturated) carbon or at (less often) an aromatic or other unsaturated carbon centre.

Nucleophilic substitution at saturated carbon centres

SN1 and SN2 reactions

In 1935, Edward D. Hughes and Sir Christopher Ingold studied nucleophilic substitution reactions of alkyl halides and related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms are the SN1 reaction and the SN2 reaction. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction.

In the SN2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. SN2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the SN1 reaction involves two steps. SN1 reactions tend to be important when the central carbon atom of the substrate is surrounded by bulky groups, both because such groups interfere sterically with the SN2 reaction (discussed above) and because a highly substituted carbon forms a stable carbocation.

Initially, the rate of the nucleophilic substitution was a little puzzling as the rate followed the pattern :

CH3X > primary > secondary < tertiary

The reaction kinetics changed from second order to first order.

The SN1 and SN2 reactions are influenced by different factors

SN1 reactivity rates follow the trend CH3X < primary < secondary < tertiary

SN2 reactivity rates follow the trend CH3X > primary > secondary > tertiary

The total reactivity is the sum of the two rates.

A graph showing the relative reactivities of the different alkyl halides towards SN1 and SN2 reactions. Also see Table 1.


Table 1. Nucleophilic substitutions on RX (an alkyl halide or equivalent)
Factor SN1 SN2 Comments
Kinetics Rate=k[RX] Rate=k[RX][Nuc]
Primary alkyl substrate Never unless
additional stabilising
groups present
Good unless
a hindered nucleophile is used
Secondary alkyl substrate Moderate Moderate
Tertiary alkyl substrate Excellent Never Elimination likely
if heated or if
strong base used
Leaving group Important Important For halogens,
I > Br > Cl >> F
Nucleophilicity Unimportant Important
Preferred solvent Polar protic Polar aprotic
Stereochemistry Racemisation
(+ partial inversion
possible)
Inversion
Rearrangements Common Rare Side reaction
Eliminations Common, especially
with basic nucleophiles
Only with heat &
basic nucleophiles
Side reaction
esp. if heated

Nucleophilic substitution reactions

There are many reactions in organic chemistry that involve this type of mechanism. Common examples include

R-XR-H using LiAlH4   (SN2)

R-Br + OHR-OH + Br (SN2) or
R-Br + H2O → R-OH + HBr   (SN1)

R-Br + OR'R-OR' + Br   (SN2)

Other mechanisms

Besides SN1 and SN2, other mechanisms are known, although they are less common. The SNi mechanism is observed in reactions of thionyl chloride with alcohols, and it is similar to SN1 except that the nucleophile is delivered from the same side as the leaving group.

Nucleophilic substitutions can be accompanied by an allylic rearrangement as seen in reactions such as the Ferrier rearrangement. This type of mechanism is called an SN1' or SN2' reaction (depending on the kinetics). With allylic halides or sulphonates, for example, the nucleophile may attack at the γ unsaturated carbon in place of the carbon bearing the leaving group. This may be seen in the reaction of 1-chloro-2-butene with sodium hydroxide to give a mixture of 2-buten-1-ol and 1-buten-3-ol:

CH3CH=CH-CH2-Cl → CH3CH=CH-CH2-OH + CH3CH(OH)-CH=CH2

The Sn1CB mechanism appears in inorganic chemistry.

Nucleophilic substitution at unsaturated carbon centres

Nucleophilic substitution via the SN1 or SN2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the nucleophilic aromatic substitution article.

When the substitution occurs at the carbonyl group, the acyl group may undergo nucleophilic acyl substitution. This is the normal mode of substitution with carboxylic acid derivatives such as acyl chlorides, esters and amides.

See also

Notes

References

  • J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992.
  • J. P. Clayden, N. Greeves, S. Warren, P. D. Wothers, Organic Chemistry, Oxford University Press, Oxford, UK, 2001.
  • R. A. Rossi, R. H. de Rossi, ''Aromatic Substitution by the SRN1 Mechanism, ACS Monograph Series No. 178, American Chemical Society, 1983. [ISBN 0-8412-0648-1]

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