Nucleophilic substitution

In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive atom is referred to as an electrophile.^[1][2]

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 a saturated aliphatic carbon or at (less often) a saturated aromatic or other unsaturated carbon centre.^[3]

Nucleophilic substitution at saturated carbon centres

S_N1 and S_N2 reactions

A graph showing the relative reactivities of the different alkyl halides towards S_N1 and S_N2 reactions (also see Table 1).

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 S_N1 reaction and the S_N2 reaction. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction.^[4]

In the S_N2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. S_N2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the S_N1 reaction involves two steps. S_N1 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 S_N2 reaction (discussed above) and because a highly substituted carbon forms a stable carbocation.

An example of a substitution reaction taking place by a so-called borderline mechanism as originally studied by Hughes and Ingold ^[5] is the reaction of 1-phenylethyl chloride with sodium methoxide in methanol.

The reaction rate is found to the sum of S_N1 and S_N2 components with 61% (3,5 M , 70°C) taking place by the latter.

Nucleophilic substitution at carbon
SN1 mechanism	SN2 mechanism

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	Never unless additional stabilising groups present	Good unless a hindered nucleophile is used
Secondary alkyl	Moderate	Moderate
Tertiary alkyl	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

• Organic reductions with hydrides, for example

R-X → R-H using LiAlH₄   (S_N2)

• hydrolysis reactions such as

R-Br + OH⁻ → R-OH + Br⁻ (S_N2) or

R-Br + H₂O → R-OH + HBr   (S_N1)

• Williamson ether synthesis

R-Br + OR'⁻ → R-OR' + Br⁻   (S_N2)

• The Wenker synthesis, a ring-closing reaction of aminoalcohols.
• The Finkelstein reaction, a halide exchange reaction. Phosphorus nucleophiles appear in the Perkow reaction and the Michaelis–Arbuzov reaction.
• The Kolbe nitrile synthesis, the reaction of alkyl halides with cyanides.

Other mechanisms

Besides S_N1 and S_N2, other mechanisms are known, although they are less common. The S_Ni mechanism is observed in reactions of thionyl chloride with alcohols, and it is similar to S_N1 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 S_N1' or S_N2' 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. Competing mechanisms exist.^[6][7]

Nucleophilic substitution at unsaturated carbon centres

Nucleophilic substitution via the S_N1 or S_N2 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.

References

1. ^ J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992.
2. ^ R. A. Rossi, R. H. de Rossi, Aromatic Substitution by the S_RN1 Mechanism, ACS Monograph Series No. 178, American Chemical Society, 1983. [ISBN 0-8412-0648-1]
3. ^ L. G. Wade, Organic Chemistry, 5th ed., Prentice Hall, Upper Saddle RIver, New Jersey, 2003.
4. ^ S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973. [ISBN 0-521-09801-7]
5. ^ 253. Reaction kinetics and the Walden inversion. Part II. Homogeneous hydrolysis, alcoholysis, and ammonolysis of -phenylethyl halidesEdward D. Hughes, Christopher K. Ingold and Alan D. Scott, J. Chem. Soc., 1937, 1201 doi:10.1039/JR9370001201
6. ^ N.S.Imyanitov. Electrophilic Bimolecular Substitution as an Alternative to Nucleophilic Monomolecular Substitution in Inorganic and Organic Chemistry. J. Gen. Chem. USSR (Engl. Transl.) 1990; 60 (3); 417-419.
7. ^ Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary