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Based on McMurry’s Organic Chemistry, 6th edition

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

2 Alkyl Halides React with Nucleophiles and Bases
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 also Brønsted bases can produce elimination

3 11.1 The Discovery of the Walden Inversion
In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents This established that optical rotation was directly related to chirality and that it changes with chemical alteration Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic acid The reaction series starting with (+) malic acid gives (-) acid

4 Reactions of the Walden Inversion

5 Significance of the Walden Inversion
The reactions alter the configuration at the chirality center The reactions involve substitution at that center Therefore, nucleophilic substitution can invert the configuration at a chirality center The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

6 11.2 Stereochemistry of Nucleophilic Substitution
In the 1920’s and 1930’s Kenyon and Phillips carried out a series of experiments to find out how inversion occurs and determine the precise mechanism of nucleophilic substitution reactions. Instead of halides they used tosylates (OTos) which are better “leaving groups” than halides. (alkyl toluene sulfonates)

7 Only the second and fifth steps are reactions at carbon So inversion certainly occurs in these substitution steps

8 Problem 11.1 Write a stereochemical equation for this nucleophilic substitution reaction: (S)-2-bromohexane + CH3COO- 

9 11.3 Kinetics of Nucleophilic Substitution
Rate is change in concentration with time Depends on concentration(s), temperature, inherent nature of reaction (activation energy) A rate law describes relationship between the concentration of reactants and rate of conversion to products – determined by experiment. A rate constant (k) is the proportionality factor between concentration and rate Example: for S  P an experiment might find Rate = k [S] (first order)

10 Reaction Kinetics Experiments show that for the reaction
The study of rates of reactions is called kinetics Rates decrease as concentrations decrease but the rate constant does not The rate law depends on the mechanism The order of a reaction is sum of the exponents of the concentrations in the rate law – the example below is second order Experiments show that for the reaction OH- + CH3Br  CH3OH + Br- Rate = k[OH-][CH3Br]

11 11.4 The SN2 Reaction One type of nucleophilic substitution reaction has the following characteristics: Reaction occurs with inversion at reacting center Follows second order reaction kinetics rate = k [Nu:-][RX] Nomenclature suggested by Hughes and Ingold in 1937: S=substitution N (subscript) = nucleophilic 2 = bimolecular - both nucleophile and substrate in rate determining step


13 SN2 Transition State The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups


15 11.5 Characteristics of the SN2 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)

16 Reactant and Transition-state Energy Levels
Higher reactant energy level (red curve) = faster reaction (smaller G‡). Higher transition-state energy level (red curve) = slower reaction (larger G‡).

17 Steric Effects on SN2 Reactions
The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 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 SN2 reactions.

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

19 Order of Reactivity in SN2
The more alkyl groups connected to the reacting carbon, the slower the reaction

20 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


22 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


24 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

25 Poor Leaving Groups Problem 11.6 Rank in order of SN2 reactivity
If a group is very basic or very small, it is prevents reaction Problem Rank in order of SN2 reactivity CH3Br, CH3OTs, (CH3)3Cl, (CH3)2CHCl

26 The Solvent Solvents that can donate hydrogen bonds (-OH or –NH) slow SN2 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

27 Problem 11.7 Benzene, ether, chloroform are not protic or very polar. How would they affect SN2 reactions?




31 11.6 The SN1 Reaction Previously we learned that tertiary alkyl halides react extremely slowly in SN2 reactions. But tert-butyl bromide reacts with water 1,000,000 times faster than methyl bromide. 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 SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step


33 SN1 Energy Diagram Step through highest energy point is rate-limiting
rate = k[RX]

34 Rate-Limiting Step The overall rate of a reaction is controlled by the rate of the slowest step The rate depends on the concentration of the species and the rate constant of the step The highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier) This is the not the greatest difference but the absolute highest point (Figures – the same step is rate-determining in both directions)

35 Stereochemistry of SN1 Reaction
The planar intermediate should lead to loss of chirality A free carbocation is achiral Product should be racemic

36 SN1 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 Alternative that SN2 is also occurring is unlikely

37 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


39 11.9 Characteristics of the SN1 Reaction
Tertiary alkyl halide is most reactive by this mechanism Controlled by stability of carbocation

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

41 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 SN2 mechanism


43 Effect of Leaving Group on SN1
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 H2O, which is still less reactive than halide p-Toluensulfonate (TosO-) is excellent leaving group


45 Nucleophiles in SN1 Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

46 Solvent Is Critical in SN1
Stabilizing carbocation also stabilizes associated transition state and controls rate Solvation of a carbocation by water

47 Polar Solvents Promote Ionization
Polar, protic and unreactive Lewis base solvents facilitate formation of R+ Solvent polarity is measured as dielectric polarization (P) (Table 11-3) Nonpolar solvents have low P Polar SOLVENT have high P values


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



52 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 SN1 processes

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



56 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 (one step) transfer of a proton to a base and departure of leaving group

57 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

58 E2 Reaction Kinetics One step – rate law has base and alkyl halide
Transition state bears no resemblance to reactant or product Rate = k[R-X][B] Reaction goes faster with stronger base, better leaving group

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

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

61 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

62 Practice problem 11.4 E2 rxn of

63 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 and 11-20) Equatorial groups are not in proper alignment

64 Kinetic Isotope Effect
Substitute deuterium for hydrogen at  position Effect on rate is kinetic isotope effect (kH/kD = 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

65 11.14 The E1 Reaction Competes with SN1 and E2 at 3° centers
V = k [RX]

66 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

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

68 Homework problems for Chapter 11
21 – 23, 25 (SN2 only), 26, 27, 29 – 32, 36, 37, 39 – 41 OWL for Chapter 11 due Jan 22 Problems 24, 25, 28, 34, 35, 38, 39, 46, 47, 49, 50, 55, 59, 62, 65

69 11.15 Summary of Reactivity: SN1, SN2, E1, E2
Alkyl halides undergo different reactions in competition, depending on the reacting molecule and the conditions Based on patterns, we can predict likely outcomes (See Table 11.4)






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