Presentation on theme: "Alkyl Halides React with Nucleophiles and Bases"— Presentation transcript:
1 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations
2 Alkyl Halides React with Nucleophiles and Bases Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilicNucleophiles will replace the halide in C-X bonds of many alkyl halides(reaction as Lewis base)Nucleophiles that are Brønsted bases produce eliminationd+Acts asNucleophiled+Acts asBase
3 Why this Chapter?Nucleophilic substitution, base induced elimination are among most widely occurring and versatile reaction types in organic chemistryReactions will be examined closely to see:How they occurWhat their characteristics areHow they can be used
4 11.1 The Discovery of Nucleophilic Substitution Reactions:Walden Inversion In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagentsThis established that optical rotation was directly related to chirality and that it changes with chemical alterationReaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acidFurther reaction with wet silver oxide gives (+)-malic acidThe reaction series starting with (+) malic acid gives (-) acid
5 Reactions of the Walden Inversion The reactions alter the array at the chirality centerThe reactions involve substitution at that centerTherefore, nucleophilic substitution can invert the configuration at a chirality centerThe presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle
6 Another Example: (+)-1-phenyl-2-propanol (-)-1-phenyl-2-propanol Used Tosylate as an excellent leaving group
7 Kinetics of Nucleophilic Substitution Rate (V) = change in concentration with timeDepends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface)A rate law describes relationship between the concentration of reactants and conversion to productsThe rate law is a result of the mechanismA rate constant (k) is the proportionality factor between concentration and rateKinetics = The study of rates of reactionsRates ↓ as concentrations ↓ but k stays sameRate units: [concentration]/time such as L/(mol x s)The order of a reaction is sum of the exponents of the concentrations in the rate law
8 Rate is dependant on both Nucleophile & Substrate 11.2 The SN2 ReactionReaction is with inversion at reacting centerFollows second order reaction kineticsIngold nomenclature to describe characteristic step:S=substitution; N (subscript) = nucleophilic; 2 = both nucleophile and substrate in characteristic step (bimolecular)Rate is dependant on both Nucleophile & SubstrateRate = k [CH3-Br] [HO-]
9 SN2 ProcessThe reaction involves a transition state in which both reactants are together
10 SN2 Transition StateThe transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups
11 Reactant and Transition State Energy Levels Affect Rate 11.3 Characteristics of the SN2 RxnReactant and Transition State Energy Levels Affect RateHigher reactant energy level (red curve) = faster reaction (smaller G‡).Higher transition state energy level (red curve) = slower reaction (larger G‡).
12 The Substrate: Steric Effects on SN2 Reactions SN2 Sensitive to steric effectsThe carbon atom in (a) bromomethane is readily accessibleresulting 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.
13 The Substrate: Steric Effects : Order of Reactivity in SN2 SN2 Sensitive to steric effectsNo reaction at C=C (vinyl or Aryl halides)
14 The Nucleophile: in SN2 Neutral or negatively charged Lewis base Reaction increases coordination at nucleophileNeutral nucleophile acquires positive chargeAnionic nucleophile becomes neutrald+d+
15 The Nucleophile: Relative Reactivity in SN2 NucleophilesDepends on reaction and conditionsMore basic nucleophiles react fasterBetter nucleophiles are lower in a column of the periodic tableAnions(-) are usually more reactive than neutrals
17 The Leaving Group: in SN2 Stable anions that are weak bases are usually excellent leaving groups and can delocalize chargevery basic or very small grps are poor leaving groups.Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.
18 The Leaving Group: in SN2 -OH needs to be turned into a good leaving group.So can convert to aClBrTosWhich are excellent leaving groups.(p-toluenesufonylchloridep-TosCl)
19 The Leaving Group: in SN2 O of the epoxide can be turned into a good leaving group so epoxide can be opened with a weak nucleophile.Addition of an acid (H+) will make epoxide C’s more electrophilic.Cl- attacks less hindered site.(If choice of epoxide C’s is 1o or 2o then major product is from attack at less hindered 1oIf choice of epoxide C’s is 1o vs 3o then major product is from attack at more + 3o)d+d+
20 Caged nucleophiles can’t attack so well The Solvent: in SN2Solvents that can donate hydrogen bonds (protic) (-OH or –NH) slow SN2 reactions by associating with reactantsEnergy is required to break interactions between reactant and solventCaged nucleophiles can’t attack so well
21 The Solvent: in SN2 Poor for SN2 Good for SN2 Protic solvents (with -OH or –NH) slow SN2 reactions by complexing with reactantsPolar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit fast SN2 reactions
22 11.4 The SN1 ReactionTertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile
23 The reaction involves a planar carbocation intermediate SN1 ReactionThe reaction involves a planar carbocation intermediate
24 SN1 Energy Diagram Rate = k [RX] Called an SN1 reaction since rate is dependant only on substrateSN1 occurs in two distinct steps while SN2 occurs with both events in same stepRate = k [RX]The slowest step (Rate-determining step) is formation of the carbocation intermediate
25 Stereochemistry of SN1 Reaction The planar intermediate leads to loss of chirality since a free carbocation is achiralNucleophile can attack either face of planar carbocationProduct is racemic or has some inversion
26 Stereochemistry of SN1 Reaction Carbocation is biased to react on side opposite leaving groupSuggests reaction occurs with carbocation loosely associated with leaving group (in an ion pair) during nucleophilic addition
27 Stereochemistry of SN1 Reaction: Effects of Ion Pair Formation If leaving group remains associated, then product has more inversion than retentionProduct is only partially racemic with more inversion than retentionAssociated carbocation and leaving group is an ion pair
29 Learning Check:The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred?
30 Solution:The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred?x 100 = 9.9 % inverted+53.6So: 90.1 % racemic
31 11.5 Characteristics of the SN1 Rxn Substrate: in SN1Ability to form stable carbocation intermediate bestTertiary alkyl halide is most reactive by this mechanismRemember Hammond postulate,”Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate”
32 Substrate: in SN1 Allylic and Benzylic Halides Allylic and benzylic intermediates stabilized by delocalization of charge
33 Learning Check:Rank the following substances in order of their expected SN1 reactivity:
34 Solution:Rank the following substances in order of their expected SN1 reactivity:1423
35 Leaving Group: in SN1 Critically dependent on leaving group the larger halides ions are better leaving groupsH2O, formed when OH of an alcohol is protonated in acidp-Toluensulfonate (TosO-) is excellent leaving groupA leaving group won’t leave unless it’s stable on its own.(Weak conjugate bases of strong acids make great leaving groups).
36 Leaving Group: in SN1H2O leaving group formed when OH of alcohol is protonated in acidrdsNucleophile attacks after rds
37 Nucleophiles: in SN1SN1 Reaction rate is not normally affected by nature or concentration of nucleophile since nucleophilic addition occurs after formation of carbocation.Once the carbocation is formed the rest is quick and easy regardless of nature of nucleophile.
38 The Solvent: in SN1Solvents that stabilize the carbocation intermediate and also transition state and speeds rateSN1 reactions go faster with polar protic solvents that cage the carbocation intermediate.
39 The Solvent: in SN1 Polar Solvents Promote Ionization Polar, protic and unreactive Lewis base solvents facilitate R+ formation
40 Learning Check:Predict whether the following reactions is more likely to be SN1 or SN2.
41 Solution:Predict whether the following reactions is more likely to be SN1 or SN2.2o benzylic; forms stable carbocations or can be attacked from behindGood leaving groupSN1Good nucleophilePolar protic solvent1o; easily attacked from behind; wouldn’t give stable carbocationGood leaving groupSN2Good nucleophilePolar aprotic solvent
42 Learning Check:Predict whether the following reactions is more likely to be SN1 or SN2.
43 Solution:Predict whether the following reactions is more likely to be SN1 or SN2.SN2SN11o allylic; forms stable carbocations or can be attacked from behind2o allylic; forms stable carbocations or can be attacked from behindGood leaving groupGood leaving group after protonation with H+Strong nucleophileWeak nucleophilePolar aprotic solventWould not stabilize a carbocation intermediatePolar protic solventStabilizes carbocation intermediate
44 11.6 Biological Substitution Rxns SN1 and SN2 reactions are common in biochemistryUnlike in the laboratory, substrate in biological substitutions is often organodiphosphate rather than an alkyl halide
45 Biological Substitution: Examples SN1SN1E1Biosynthesis of Geraniol in Roses
46 Biological Substitution: Examples SN2Biosynthesis of Adrenaline
47 11.7 Elimination Reactions: of Alkyl Halides Opposite of additionGenerates an alkeneCan compete with substitution and decrease yield, especially for SN1 processes
48 Elimination Reactions: E1 Competes with SN1Favored over SN1 when have poor Nu- that can still be a base
49 Elimination Reactions: E1 Example Competes with SN1Favored over SN1 when have poor Nu- that can still be a baseSN1E1
50 Elimination Rxns: Zaitsev’s Rule In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates
51 Elimination Reactions: E2 Competes with SN2Favored over SN2 when have strong base and steric hinderance
52 11.8 The E2 Reaction: Mechanism Base grabs H that is anti-periplanar to leaving groupTransition state combinesleaving of X and transfer of HProduct alkene forms stereospecifically
53 The E2 Rxn: Deuterium Isotope Effect In RDS Breaking of C-H bond is slower than breaking of C-D bond.
54 Elimination Rxns: E2 Stereochemistry Overlap of the developing orbital in the transition state requires anti-periplanar geometry so electrons can give back-side SN2 type attack.
55 Elimination Rxns: Predicting E2 Products E2 is stereospecificMeso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenylcis 1,2-diphenyl product
56 Elimination Rxns: Predicting E2 Products E2 is stereospecificRR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenylSSTrans 1,2 diphenyl product
57 11.9 The E2 Rxn: Cyclohexene Formation Abstracted proton and leaving group should align trans-diaxial to be anti periplanar in approaching transition stateEquatorial groups are not in proper alignment
58 The E2 Rxn: Cyclohexene Formation Example Fast200 x’s slower sinceRing must flip to less stable ring conformation in order to get anti-periplanar E2
59 Comparing E1 and E2 Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is notE1 gives Zaitsev orientation
61 E1cB ReactionTakes place through a carbanion intermediate
62 11.11 Biological Elimination Rxns All three elimination reactions occur in biological pathwaysE1cB very commonTypical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioesterE1cB
63 11.12 Summary of Reactivity: SN1, SN1, E1,E1cB, E2
64 Summary of Reactivity: SN1, SN1, E1,E1cB, E2 Strongly basic nucleophiles give more elimination as steric bulk increases.Primary halides with strongly basic nucleophiles give mostly SN2 products.Branched halides with strongly basic nucleophiles give about 50/50 SN2 and E2 products.Tertiary halides with strongly basic nucleophiles give exclusive E2 products. With neutral or weakly basic nucleophiles SN1 and E1 pathways compete.
66 Unimolecular Substitution in Polar Media - Important ConceptsUnimolecular Substitution in Polar Media -Secondary haloalkanes: slowTertiary haloalkanes: fastWhen the solvent is the nucleophile, the process is called solvolysis.Rate Determining Step in Unimolecular Substitution -Dissociation of the C-X bond to form a carbocation intermediate.Added strong nucleophile changes the product but not the reaction rate.Carbocation Stabilization by Hyperconjugation: Tertiary > Secondary. Primary and methyl unstable.
67 Important ConceptsRacemization - Often occurs upon unimolecular substitution at a chiral carbon.Unimolecular Elimination – Alkene formation accompanies substitution in secondary and tertiary system.Bimolecular Elimination - May result from high concentrations of strong base. The elimination involves the anti conformational arrangement of the leaving group and the extracted hydrogen.Substitution Favored - by unhindered substrates and small, less basic nucleophilesElimination Favored - by hindered substrates and bulky, more basic nucleophiles.
68 Which of the following is the product of the SN2 reaction between the hydroxide ion (HO–) and (R)-CH3–CHDI? D = 2H (deuterium)22.214.171.124.5.12345
69 Consider the reaction of (S)-(–)-1-iodo-2-methylbutane to produce (+)-2-methyl-1-butanol. What is the absolute configuration of the product?RSR and S (racemic mixture)R and S (unequal amounts)There is no chiral center in the product
70 Which of the following SN2 reactions is expected to have the highest rate? methyl bromide with water in DMSOethyl bromide with chloride in methanolethyl bromide with hydroxide in HMPAethyl chloride with ammonia in acetonitrilemethyl bromide with hydrosulfide (HS–) in HMPA
71 It cannot be determined. When A and B react in t-BuOH, the above rate expression is observed. What is the most likely mechanism of this reaction?E2SN2E1SN1It cannot be determined.
72 What is the main reason that polar aprotic solvents are favored over polar protic solvents for SN2 reactions?Polar aprotic solvents dissolve nucleophiles more readily than polar protic solvents.Polar aprotic solvents destabilize anions.Polar aprotic solvents stabilize cations, including carbocations.Polar aprotic solvents form stabilizing hydrogen bonds.Polar aprotic solvents prevent rearrangements from occurring.
73 What statement about the SN2 reaction of methyl bromide with hydroxide is incorrect? The reaction kinetics is first-order in hydroxide.In the transition state the carbon is sp2 hybridized.Absolute configuration is inverted from R to S.The reaction is faster in HMPA than in water.The reaction can be catalyzed by I–.
74 Select the substrate which would react fastest in the substitution reaction. 126.96.36.199.5.12345
75 Which electrophile will react the fastest by the SN2 mechanism with cyanide (NC–) in DMF? phenyl iodide (Ph–I)vinyl tosylate (H2C=CH–OTos)ethyl bromidecyclohexyl bromidebenzyl tosylate (Ph-CH2-OTos)
76 Which of the following reagents is the best nucleophile for an SN2 reaction? methanolmethoxideacetatehydroxidewater
77 Which set of reaction conditions represents the best way to carry out the following transformation? AcOHNaOAc in AcOHNaOAc in H2ONaOAc in DMSOAcOH in HMPA
78 Which of the following will give the fastest SN1 reaction? 188.8.131.52.4.12345
79 In a reaction between an alkyl halide and methoxide, doubling the alkyl halide concentration doubles the rate of the reaction. Which of the following is a reasonable conclusion?The reaction is an SN2 process.The reaction proceeds by the SN1 mechanism.The observation indicates an E2 process.This is a reaction with E1 mechanism.None of these
80 Which compound would serve as the best starting material for the transformation shown below? 184.108.40.206.5.12345
81 Including stereoisomers, how many products are possible from the following reaction? 12345
82 What mechanism is most likely to operate for the following reaction? SN1SN2E1E2E1cB
83 Select the reagent and solvent combination which would result in the fastest rate of substitution (R = CH3 in all cases).ROH, HMPARS–, H2ORO–, H2ORS–, DMSORSH, H2O
84 Which of the following is the best nucleophile? (CH3)3N(CH3)2P–(CH3)2OCH3O–
85 What is the major product of the following reaction? 220.127.116.11.5.12345
86 What is the most likely product of the following reaction? 18.104.22.168.5.12345
87 Which of the two stereoisomers of 4-t-butylcyclohexyl iodide (127I) will undergo SN2 substitution with 128I– faster, and why?A will react faster because it is more stableB will react faster because it gives a more stable product.A will react faster because nucleophile’s approach from the bottom face of the molecule is easier for steric reasons.A and B will react with the same rate because the transition states for both reactions are the same.B will react faster because it is less stable than A, and the transition state for both reactions is of the same energy.