Nucleophilic substitution

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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 to replace a so-called leaving group; the positive or partially positive atom is referred to as an electrophile. The whole molecular entity of which the electrophile and the leaving group are part is usually called the substrate.[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 basic 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) an aromatic or other unsaturated carbon centre.[3]

Saturated carbon centres[edit]

SN1 and SN2 reactions[edit]

A graph showing the relative reactivities of the different alkyl halides towards SN1 and SN2 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 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.[4]

In the SN2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously (ie. concerted reaction). 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.

The main difference between SN1 reactions and SN2 reactions is that SN1 reactions are determined by the carbon skeleton and the leaving group, but not the nucleophile, while the SN2 reaction is determined by the carbon skeleton, leaving group and nucleophile. One reason for this is that in the SN1 reaction, the leaving group must be "good" enough to leave and this is the slowest step. After the leaving group leaves the process of nuclephilic attack on the carbocation is very fast and not rate-determining. However in the SN2 reaction, the nucleophile attacks at almost the same time as the leaving group leaves, so both the nucleophile and electrophile must be considered as a factor.

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.

1-phenylethylchloride methanolysis

The reaction rate is found to the sum of SN1 and SN2 components with 61% (3,5 M, 70 °C) taking place by the latter.

Nucleophilic substitution at carbon
SN1 reaction mechanism SN2 reaction mechanism
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

Reactions[edit]

There are many reactions in organic chemistry 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[edit]

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. Competing mechanisms exist.[6][7]

In organometallic chemistry the nucleophilic abstraction reaction occurs with a nucleophilic substitution mechanism.

Unsaturated carbon centres[edit]

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.

References[edit]

  1. ^ J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992.
  2. ^ 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].
  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