Nucleophilic substitution

Inchemistry,anucleophilic substitution(S_N) is a class ofchemical reactionsin which anelectron-richchemical species(known as anucleophile) replaces afunctional groupwithin another electron-deficient molecule (known as theelectrophile). The molecule that contains the electrophile and the leaving functional group is called thesubstrate.

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)attacksthe substrate (R−LG) and bonds with it. Simultaneously, the leaving group (LG) departs with an electron pair. The principal product in this case isR−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 thehydrolysisof analkylbromide,R-Br under basic conditions, where the attacking nucleophile ishydroxyl(OH⁻) and theleaving groupisbromide(Br⁻).

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

Nucleophilic substitution reactions are common inorganic chemistry.Nucleophiles often attack asaturatedaliphaticcarbon. Less often, they may attack anaromaticor unsaturated carbon.

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. HughesandSir Christopher Ingoldstudied nucleophilic substitution reactions ofalkyl halidesand related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms were theS_N1 reactionand theS_N2 reaction,whereSstands for substitution,Nstands for nucleophilic, and the number represents thekinetic orderof the reaction.

In the S_N2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously (i.e. aconcerted reaction). S_N2 occurs when the central carbon atom is easily accessible to the nucleophile.

Nucleophilic substitution at carbon
SN2 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, anaprotic solventis 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 effectsdrive 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 stablecarbocation.

Nucleophilic substitution at carbon
SN1 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	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	Eliminationlikely if heated or if strong base used
Leaving group	Important	Important	For halogens, I > Br > Cl >> F
Nucleophilicity	Unimportant	Important
Preferredsolvent	Polarprotic	Polaraprotic
Stereochemistry	Racemisation(+ partialinversionpossible)	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 reductionswithhydrides,for example

R−X→R−HusingLiAlH₄(S_N2)

• Hydrolysisreactions 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)

• TheWenker synthesis,a ring-closing reaction of aminoalcohols.
• TheFinkelstein reaction,a halide exchange reaction. Phosphorus nucleophiles appear in thePerkow reactionand theMichaelis–Arbuzov reaction.
• TheKolbe nitrile synthesis,the reaction of alkyl halides with cyanides.

Borderline mechanism

An example of a substitution reaction taking place by a so-calledborderline mechanismas originally studied by Hughes and Ingoldis the reaction of1-phenylethyl chloridewithsodium methoxidein methanol.

Thereaction rateis 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. TheS_Nimechanism is observed in reactions ofthionyl chloridewithalcohols,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 anallylic rearrangementas seen in reactions such as theFerrier rearrangement.This type of mechanism is called an S_N1' or S_N2' reaction (depending on the kinetics). Withallylichalides 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 withsodium hydroxideto give a mixture of 2-buten-1-ol and 1-buten-3-ol:

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

TheSn1CB mechanismappears ininorganic chemistry.Competing mechanisms exist.

Inorganometallic chemistrythenucleophilic abstractionreaction 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 thenucleophilic aromatic substitutionarticle.

Substitution can occur at thecarbonylgroup, such asacyl chloridesandesters.