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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 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 SN1 and SN2 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 SN2 Process The reaction involves a transition state in which both reactants are together

8 “Walden” Inversion

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

10 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.

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

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

13 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)

14 The SN1 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 SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step

15 Stereochemistry of SN1 Reaction
The planar intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion

16 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

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 SN1 Energy Diagram Step through highest energy point is rate-limiting (k1 in forward direction) k1 k-1 k2 V = k[RX] Rate-determining step is formation of carbocation

19 11.9 Characteristics of the SN1 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
SN1 Two steps with carbocation intermediate Occurs in 3°, allyl, benzyl SN2 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 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

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 SN2 mechanism


31 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


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 SN1
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 Polar aprotic solvents solvate cations well, anions poorly
+ - Cl + + + + - + - + - + Na + + - good fit! bad fit!

39 SN1: Carbocation not very encumbered, but needs to be solvated in rate determining step
(slow) Polar protic solvents are good because they solvate both the leaving group and the carbocation in the rate determining step k1! The rate k2 is somewhat reduced if the nucleophile is highly solvated, but this doesn’t matter since k2 is inherently fast and not rate determining.

40 SN2: 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 SN1 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 SN1 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 and 11-20) Equatorial groups are not in proper alignment

52 11.14 The E1 Reaction Competes with SN1 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: 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



58 Special cases, both SN1 and SN2 blocked (or exceedingly slow)
Carbocation highly unstable, attack from behind blocked Carbocation can’t flatten out as required by sp2 hybridization, attack from behind blocked Also: elimination not possible, can’t place double bond at bridgehead in small cages (“Bredt’s rule”) Carbocation highly unstable, attack from behind blocked Carbocation would be primary, attack from behind difficult due to steric blockage

59 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





64 31 januari 2010

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