Nucleophilic substitution

In chemistry, a nucleophilic substitution is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). The molecule that contains the electrophile and the leaving functional group is called the substrate.[1][2]

The most general form of the reaction may be given as the following:

{\text{Nuc}}\mathbf {:} +{\ce {R-LG -> R-Nuc}}+{\text{LG}}\mathbf {:}

The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R−LG) and bonds with it. Simultaneously, 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 hydroxyl (OH⁻) and the leaving group is bromide (Br⁻).

{\ce {R-Br + OH- -> R-OH + Br-}}

Nucleophilic substitution reactions are common in organic chemistry. Nucleophiles often attack a saturated aliphatic carbon. Less often, they may attack an aromatic or unsaturated carbon.[3]

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 were the S_N1 reaction and the S_N2 reaction, where S stands for 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 (i.e. a concerted reaction). S_N2 occurs when the central carbon atom is easily accessible to the nucleophile.[5]

Nucleophilic substitution at carbon


S_N2 mechanism

In S_N2 reactions, there are a few conditions that affect the rate of the reaction. First of all, the 2 in S_N2 implies that there are two concentrations of substances that affect the rate of reaction: substrate (Sub) and nucleophile. The rate equation for this reaction would be Rate=k[Sub][Nuc]. For a S_N2 reaction, an aprotic solvent is best, such as acetone, DMF, or DMSO. Aprotic solvents do not add protons (H⁺ ions) into solution; if protons were present in S_N2 reactions, they would react with the nucleophile and severely limit the reaction rate. Since this reaction occurs in one step, steric effects drive the reaction speed. In the intermediate step, the nucleophile is 185 degrees from the leaving group and the stereochemistry is inverted as the nucleophile bonds to make the product. Also, because the intermediate is partially bonded to the nucleophile and leaving group, there is no time for the substrate to rearrange itself: the nucleophile will bond to the same carbon that the leaving group was attached to. A final factor that affects reaction rate is nucleophilicity; the nucleophile must attack an atom other than a hydrogen.

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.

Nucleophilic substitution at carbon

S_N1 mechanism

Like S_N2 reactions, there are quite a few factors that affect the reaction rate of S_N1 reactions. Instead of having two concentrations that affect the reaction rate, there is only one, substrate. The rate equation for this would be Rate=k[Sub]. Since the rate of a reaction is only determined by its slowest step, the rate at which the leaving group "leaves" determines the speed of the reaction. This means that the better the leaving group, the faster the reaction rate. A general rule for what makes a good leaving group is the weaker the conjugate base, the better the leaving group. In this case, halogens are going to be the best leaving groups, while compounds such as amines, hydrogen, and alkanes are going to be quite poor leaving groups. As S_N2 reactions were affected by sterics, S_N1 reactions are determined by bulky groups attached to the carbocation. Since there is an intermediate that actually contains a positive charge, bulky groups attached are going to help stabilize the charge on the carbocation through resonance and distribution of charge. In this case, tertiary carbocation will react faster than a secondary which will react much faster than a primary. It is also due to this carbocation intermediate that the product does not have to have inversion. The nucleophile can attack from the top or the bottom and therefore create a racemic product. It is important to use a protic solvent, water and alcohols, since an aprotic solvent could attack the intermediate and cause unwanted product. It does not matter if the hydrogens from the protic solvent react with the nucleophile since the nucleophile is not involved in the rate determining step.

Table 1. Nucleophilic substitutions on RX (an alkyl halide or equivalent)
Factor	S_N1	S_N2	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

There are many reactions in organic chemistry involving 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.

Borderline mechanism

An example of a substitution reaction taking place by a so-called borderline mechanism as originally studied by Hughes and Ingold[6] 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.

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:

{\ce {CH3CH=CH-CH2-Cl -> CH3CH=CH-CH2-OH + CH3CH(OH)-CH=CH2}}

The Sn1CB mechanism appears in inorganic chemistry. Competing mechanisms exist.[7][8]

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

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

March, J. (1992). Advanced Organic Chemistry (4th ed.). New York: Wiley. ISBN 9780471601807.
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.
L. G. Wade, Organic Chemistry, 5th ed., Prentice Hall, Upper Saddle River, New Jersey, 2003.
S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973. ISBN 0-521-09801-7
Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles Timothy P. Curran, Amelia J. Mostovoy, Margaret E. Curran, and Clara Berger Journal of Chemical Education 2016 93 (4), 757-761 doi:10.1021/acs.jchemed.5b00394
253. Reaction kinetics and the Walden inversion. Part II. Homogeneous hydrolysis, alcoholysis, and ammonolysis of -phenylethyl halides Edward D. Hughes, Christopher K. Ingold and Alan D. Scott, J. Chem. Soc., 1937, 1201 doi:10.1039/JR9370001201
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.
Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary

External links

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[1] March, J. (1992). Advanced Organic Chemistry (4th ed.). New York: Wiley. ISBN 9780471601807.

[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] Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles Timothy P. Curran, Amelia J. Mostovoy, Margaret E. Curran, and Clara Berger Journal of Chemical Education 2016 93 (4), 757-761 doi:10.1021/acs.jchemed.5b00394

[6] 253. Reaction kinetics and the Walden inversion. Part II. Homogeneous hydrolysis, alcoholysis, and ammonolysis of -phenylethyl halides Edward D. Hughes, Christopher K. Ingold and Alan D. Scott, J. Chem. Soc., 1937, 1201 doi:10.1039/JR9370001201

[7] 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.

[8] Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary

Basic reaction mechanisms
Nucleophilic substitutions	Unimolecular nucleophilic substitution (S_N1) Bimolecular nucleophilic substitution (S_N2) Nucleophilic aromatic substitution (S_NAr) Nucleophilic internal substitution (S_Ni) Nucleophilic acyl substitution (S_NAcyl)
Electrophilic substitutions	Electrophilic aromatic substitution (S_EAr)
Elimination reactions	Unimolecular elimination (E1) E1cB-elimination Bimolecular elimination (E2) E_i elimination
Addition reactions	Electrophilic addition Nucleophilic addition Free-radical addition Cycloaddition Oxidative addition
Unimolecular reactions	Intramolecular reaction Isomerization Photodissociation Lindemann–Hinshelwood mechanism RRKM theory
Electron/Proton transfer reactions	Redox Harpoon reaction Grotthuss mechanism Marcus theory Inner sphere electron transfer Outer sphere electron transfer
Medium effects	Solvent effects Cage effect Matrix isolation
Related topics	Elementary reaction Reaction dynamics Reactive intermediate Radical (chemistry) Molecularity Stereochemistry Catalysis Collision theory Arrow pushing Potential energy surface
Chemical kinetics	Rate equation Equilibrium constant Rate-determining step Reaction coordinate Energy profile (chemistry) Transition state theory Activation energy Activated complex Arrhenius equation Eyring equation Michaelis–Menten kinetics Diffusion-controlled reaction