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Chemistry 2131:
Organic Chemistry for the Life Sciences(3)

Nucleophilic Substitution Reactions

• an important class of reactions is nucleophilic substitution. The most obvious group of compounds to undergo nucleophilic substitution are the alkyl halides.
• alkyl halides are alkanes with halides atoms covalently bonded to sp³ hybridized carbon atoms
• the nomenclature of this class of compounds is simple and is derived from the name of the parent alkane. The halogen prefixes fluoro-, chloro, bromo, and iodo are used to indicate the presence of a halogen group.
• the numbering of the parent chain gives the first substituent, be it an alkyl group or a halide atom, the lowest number
• the halide groups are listed with the alkyl groups in alphabetical order. For example, 3-bromo-2-methylpentane... The usual prefixes di-, tri-, tetra... apply, for example 2,3-dichlorobutane
• if a double bond or other functional group of priority is present, the halide is numbered accordingly. For example, 4-bromocyclohexene.
• getting back to nucleophilic substitution, this reaction involves the replacement of one nucleophilic group for another. Remember that a nucleophile is a reagent that donates an unshared electron pair to form a new bond, it is electron rich, it is acting as a Lewis base.
• there are 2 principal reaction mechanisms called S_N1 and S_N2. These names stand for "substitution nucleophilic unimolecular" and "substitution nucleophilic bimolecular".
• the major difference between these mechanisms is the timing of carbon-halide bond breakage and the carbon-nucleophile bond formation.

2. S_N1:

• the hallmark of the S_N1 reaction is that the carbon halide bond breaks completely before the nucleophile attacks
• this is what makes the reaction a unimolecular one. Only one reactant is involved in the formation of the transition state. This means that the rate of the reaction depends on the concentration of this reactant alone
• as an example let's look at the reaction of 2-bromopropane with methanol (in methanol). The first step of the reaction is the breakage of the C-Br bond, resulting in the formation of a secondary carbocation and a bromide ion
• remember that carbocations are planar structures!
• the next step is that attack of the carbocation by a lone pair on the oxygen atom of methanol to give an oxonium ion. The proton can be removed by the bromide or by the solvent, to give isopropyl methyl ether.
• this was a typical example. So, the overall process involves bond breakage leading to the carbocation intermediate, then attack of the carbocation by the nucleophile
• what about the stereochemistry of this reaction? If the reactant alkyl halide is chiral, for example 2-bromobutane, then a racemic mixture of products is formed. Why? Remember that the carbocation is planar, so the nucleophile can attack from either side equally as well giving a mixture of stereoisomers as products.
• consider for a moment the energetics of the process. The rate limiting step is the formation of the carbocation intermediate. The transition state is the point where the halide starts to leave, then you get a slight trough where the carbocation intermediate resides, then a smaller activation energy to surmount to have the nucleophile attack and to proceed to product.
• since the rate limiting step is the formation of a carbocation intermediate, it is not surprising that halides that give more stable carbocations react more rapidly by S_N1.

3. S_N2:

• the hallmark of S_N2 is that the C-X bond breaks as the C-Nu bond forms in a concerted fashion
• this makes the reaction bimolecular, two reactants are involved in formation of the transition state.
• if we look at the example of (R)-2-bromobutane reacting with the hydroxide ion, a lone pair on oxygen attacks the carbon pushing the halide off in one concerted step.
• the transition state (not an intermediate) has the OH on one side, the Br on the other and the other groups in a plane.
• the product is 100% (S)-2-butanol and Br-.
• you always get backside attack and inversion of stereochemistry
• because of size and electron density considerations, the attacking nucleophile must come from the opposite face
• the energy diagram has only one peak, representing the formation of the transition state. The formation of this transition state depends on the concentrations of both alkyl halide and nucleophile.

4. Factors that Influence the Rates of S_N1 and S_N2 reactions:

• a number of factors influence the relative rates of these substitution reactions. We'll start by looking at the strength of the nucleophile. The effectiveness of a nucleophile can be measured and a relative scale of nucleophilicity can be arrived at.
• the strong nucleophiles include: Br-, I-, HO-, CH₃O-, RO-, CH₃S- and RS-
• moderate nucleophiles include: carboxylates, thiols, sulfides and amines
• poor or weak nucleophiles include: water, alcohols and carboxylic acids
• another factor which affects the rate of substitution reactions is the structure of the alkyl halide. S_N1 reactions are governed by electronic factors, namely the relative stability of the carbocation intermediate. Since we know that more substituted carbocations are more stable, the more highly substituted carbocations form more quickly.
• thus, tertiary halides react more quickly by S_N1 than secondary, which react more quickly than primary (which essentially doesn't react at all) and methyl.
• S_N2 reactions are governed by steric factors. The reactions are particularly sensitive to steric hindrance. Increased bulk (in space filling models) hinders access to the carbon inquestion.
• thus, the more highly substituted the halide, the more hindered it is, therefore the slower the reaction by S_N2.
• steric hindrance at the adjacent carbons can also contribute. By convention, the carbon bearing the halide is the alpha carbon, and the adjacent carbon(s) is(are) called beta. The degree of substitution of the beta carbons affects the rate of S_N2. Consider the following data:

protic solvents favour S_N1 reactions because the carbocation intermediate can form more easily in this polar solvent. aprotic solvents such as dimethylsulfoxide (DMSO), propanone (acetone), dichloromethane, and diethyl ether do not favour carbocation formation. Thus S_N2 is favoured in these solvents.