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11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations Based on McMurry’s Organic Chemistry, 6 th edition.

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Presentation on theme: "11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations Based on McMurry’s Organic Chemistry, 6 th edition."— Presentation transcript:

1 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations Based on McMurry’s Organic Chemistry, 6 th edition

2 Nucleophiles and Leaving Groups:

3 Alkyl Halides React with Nucleophiles Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilic Nucleophiles will replace the halide in C-X bonds of many alkyl halides(reaction as Lewis base) Nucleophiles that are strong Brønsted bases can produce elimination

4 Reaction Kinetics The study of rates of reactions is called kinetics The order of a reaction is sum of the exponents of the concentrations in the rate law – the first example is first order, the second one second order.

5 11.4 The S N 1 and S N 2 Reactions Follow first or second order reaction kinetics Ingold nomenclature to describe characteristic step: S=substitution N (subscript) = nucleophilic 1 = substrate in characteristic step (unimolecular) 2 = both nucleophile and substrate in characteristic step (bimolecular)

6 Stereochemical Modes of Substitution Substitution with inversion: Substitution with retention: Substitution with racemization: 50% - 50%

7 S N 2 Process The reaction involves a transition state in which both reactants are together

8 “Walden” Inversion

9 S N 2 Transition State The transition state of an S N 2 reaction has a planar arrangement of the carbon atom and the remaining three groups

10 Steric Effects on S N 2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast S N 2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower S N 2 reactions.

11 Steric Hindrance Raises Transition State Energy Steric effects destabilize transition states Severe steric effects can also destabilize ground state Very hindered

12 Order of Reactivity in S N 2 The more alkyl groups connected to the reacting carbon, the slower the reaction

13 11.5 Characteristics of the S N 2 Reaction Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides)

14 The S N 1 Reaction Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile Called an S N 1 reaction – occurs in two distinct steps while S N 2 occurs with both events in same step

15 Stereochemistry of S N 1 Reaction The planar intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion

16 S N 1 in Reality Carbocation is biased to react on side opposite leaving group Suggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition

17 Effects of Ion Pair Formation If leaving group remains associated, then product has more inversion than retention Product is only partially racemic with more inversion than retention Associated carbocation and leaving group is an ion pair

18 S N 1 Energy Diagram Rate-determining step is formation of carbocation Step through highest energy point is rate-limiting (k 1 in forward direction) k1k1 k2k2 k -1 V = k[RX]

19 11.9 Characteristics of the S N 1 Reaction Tertiary alkyl halide is most reactive by this mechanism Controlled by stability of carbocation

20 Delocalized Carbocations Delocalization of cationic charge enhances stability Primary allyl is more stable than primary alkyl Primary benzyl is more stable than allyl

21 Comparison: Substitution Mechanisms S N 1 Two steps with carbocation intermediate Occurs in 3°, allyl, benzyl S N 2 Two steps combine - without intermediate Occurs in primary, secondary

22 The Nucleophile Neutral or negatively charged Lewis base Reaction increases coordination at nucleophile Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral See Table 11-1 for an illustrative list

23 Relative Reactivity of Nucleophiles Depends on reaction and conditions More basic nucleophiles react faster (for similar structures. See Table 11-2) Better nucleophiles are lower in a column of the periodic table Anions are usually more reactive than neutrals


25 The Leaving Group A good leaving group reduces the barrier to a reaction Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge

26 “Super” Leaving Groups

27 Poor Leaving Groups If a group is very basic or very small, it is prevents reaction

28 Effect of Leaving Group on S N 1 Critically dependent on leaving group Reactivity: the larger halides ions are better leaving groups In acid, OH of an alcohol is protonated and leaving group is H 2 O, which is still less reactive than halide p-Toluensulfonate (TosO - ) is excellent leaving group

29 Allylic and Benzylic Halides Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13) Primary allylic and benzylic are also more reactive in the S N 2 mechanism


31 The Solvent Solvents that can donate hydrogen bonds (-OH or – NH) slow S N 2 reactions by associating with reactants Energy is required to break interactions between reactant and solvent Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction


33 Polar Solvents Promote Ionization Polar, protic and unreactive Lewis base solvents facilitate formation of R + Solvent polarity is measured as dielectric polarization (P)

34 Solvent Is Critical in S N 1 Stabilizing carbocation also stabilizes associated transition state and controls rate Solvation of a carbocation by water

35 Effects of Solvent on Energies Polar solvent stabilizes transition state and intermediate more than reactant and product

36 Polar aprotic solvents Form dipoles that have well localized negative sides, poorly defined positive sides. Examples: DMSO, HMPA (shown here) + - + +

37 Common polar aprotic solvents

38 + - + + + - + + + - + + + - + + Na + + - + + + - + + + - + + + - + + Cl - Polar aprotic solvents solvate cations well, anions poorly good fit! bad fit!

39 S N 1: Carbocation not very encumbered, but needs to be solvated in rate determining step Polar protic solvents are good because they solvate both the leaving group and the carbocation in the rate determining step k 1 ! The rate k 2 is somewhat reduced if the nucleophile is highly solvated, but this doesn’t matter since k 2 is inherently fast and not rate determining. (slow)

40 S N 2: Things get tight if highly solvated nucleophile tries to form pentacoordiante transition state Polar aprotic solvents favored! There is no carbocation to be solvated.

41 Nucleophiles in S N 1 Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

42 11.10 Alkyl Halides: Elimination Elimination is an alternative pathway to substitution Opposite of addition Generates an alkene Can compete with substitution and decrease yield, especially for S N 1 processes

43 Zaitsev’s Rule for Elimination Reactions (1875) In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

44 Mechanisms of Elimination Reactions Ingold nomenclature: E – “elimination” E1: X - leaves first to generate a carbocation a base abstracts a proton from the carbocation E2: Concerted transfer of a proton to a base and departure of leaving group

45 11.11 The E2 Reaction Mechanism A proton is transferred to base as leaving group begins to depart Transition state combines leaving of X and transfer of H Product alkene forms stereospecifically

46 Geometry of Elimination – E2 Antiperiplanar allows orbital overlap and minimizes steric interactions

47 E2 Stereochemistry Overlap of the developing  orbital in the transition state requires periplanar geometry, anti arrangement Allows orbital overlap


49 Predicting Product E2 is stereospecific Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenyl RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl (E)-1bromo-1,2-diphenylethene


51 11.12 Elimination From Cyclohexanes Abstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition state (see Figures 11-19 and 11-20) Equatorial groups are not in proper alignment

52 11.14 The E1 Reaction Competes with S N 1 and E2 at 3° centers V = k [RX]

53 Stereochemistry of E1 Reactions E1 is not stereospecific and there is no requirement for alignment Product has Zaitsev orientation because step that controls product is loss of proton after formation of carbocation

54 Comparing E1 and E2 Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientation

55 11.15 Summary of Reactivity: S N 1, S N 2, E 1, E 2 Alkyl halides undergo different reactions in competition, depending on the reacting molecule and the conditions Based on patterns, we can predict likely outcomes



58 Special cases, both S N 1 and S N 2 blocked (or exceedingly slow) Carbocation highly unstable, attack from behind blocked Carbocation would be primary, attack from behind difficult due to steric blockage Carbocation can’t flatten out as required by sp 2 hybridization, attack from behind blocked Also: elimination not possible, can’t place double bond at bridgehead in small cages (“Bredt’s rule”)

59 Kinetic Isotope Effect Substitute deuterium for hydrogen at  position Effect on rate is kinetic isotope effect (k H /k D = deuterium isotope effect) Rate is reduced in E2 reaction Heavier isotope bond is slower to break Shows C-H bond is broken in or before rate- limiting step





64 64 11.ppt 31 januari 2010

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