1 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Alkyl Halides and Nucleophilic Substitution

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4 Interesting Alkyl Halides

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7 Reactions of Alkyl Halides

8 Three components are necessary in any substitution reaction. General Features of a Substitution Reaction

9 When a neutral nucleophile is used, the substitution product bears a positive charge.

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12 Nucleophiles Basicity is a thermodynamic property Nucleophilicity is a kinetic property

13 Steric hindrance decreases nucleophilicity but not basicity.

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15 But what is the order of bond making and bond breaking? In theory, there are two possibilities. [1] Bond making and bond breaking occur at the same time. This is an example of an S N 2 (substitution nucleophilic bimolecular) mechanism.

16 [2] Bond breaking occurs before bond making. This is an example of an S N 1 (substitution nucleophilic unimolecular) mechanism.

S N 2 Reaction CH 3 Br + OH – CH 3 OH + Br – Rate = k[CH 3 Br][OH - ]a second-order reaction

18 All S N 2 reactions proceed with backside attack of the nucleophile, resulting in inversion of configuration at a stereogenic center.

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22 The S N 2 reaction is a key step in the laboratory synthesis of many important drugs.

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27 The rate of an S N 1 reaction is affected by the type of alkyl halide involved. This trend is exactly opposite to that observed in S N 2 reactions.

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30 The Hammond Postulate

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33 The strong nucleophile favors an S N 2 mechanism. The weak nucleophile favors an S N 1 mechanism.

34 A better leaving group increases the rate of both S N 1 and S N 2 reactions.

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In addition to substitution, an alkyl halide can undergo an elimination reaction The E2 Reaction

The Regioselectivity of the E2 Reaction The major product of an E2 reaction is the most stable alkene The greater the number of substituents, the more stable is the alkene (The Zaitsev Rule)

Potential Energies of Pentene Isomers

Consider the regioselectivity of the E2 reaction The alkene with the bulkiest groups on opposite sides of the double bond will be formed in greater yield, because it is the more stable alkene

The E1 Reaction

Elimination from Cyclic Compounds In an E2 reaction, groups to be eliminated must be trans to one another (anti-coplanar)

Competition Between Substitution and Elimination Alkyl halides can undergo S N 2, S N 1, E2 and E1 1) decide whether the reaction conditions favor S N 2/E2 or S N 1/E1 S N 2/E2 reactions are favored by a high concentration of nucleophile/strong base S N 1/E1 reactions are favored by a poor nucleophile/weak base 2) decide how much of the product will be the substitution product and how much of the product will be the elimination product

Apakah mekanisme reaksi yang berkaitan dengan reaksi berikut, substitusi S N 1 atau S N 2? Jelaskan alasan Saudara 1.(CH 3 ) 3 CBr + CH 3 OH  (CH 3 ) 3 COCH 3 + HBr 2.CH 3 CH 2 I + NaCN  CH 3 CH 2 CN + NaI