Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson 9-1 Nucleophilic Substitution and -Elimination Chapter 9 9-2 Nucleophilic Substitution - Nu: + Nucleophile C Lv nucleophilic substitution C Nu + Lv Leaving group Nucleophilic substitution: any reaction in which one nucleophile substitutes for another at a tetravalent carbon Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base 9-3 Nucleophilic Substitution Some nucleophilic substitution reactions - : : : : : : Reaction: Nu : + CH3 Br : CH3 Nu + : Br : CH3 OH an alcohol RO : CH3 OR an ether CH3 SH a thiol (a mercaptan) HC C: CH3 C CH an alkyne :C N : CH3 C N: a nitrile : : : : HO : : : : : - : : HS : - - CH3 NH3 + : : : HOH an alkyl iodide CH3 I : : : : NH3 : : : I :- CH3 O-H H + an alkylammonium ion an alcohol (after proton transfer) 9-4 Solvents Protic solvent: a solvent that is a hydrogen bond donor • the most common protic solvents contain -OH groups Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor • nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity 9-5 Dielectric Constant Solvents are classified as polar and nonpolar • the most common measure of solvent polarity is dielectric constant constant: a measure of a solvent’s ability to insulate opposite charges from one another Dielectric • the greater the value of the dielectric constant of a solvent, the smaller the interaction between ions of opposite charge dissolved in that solvent • polar solvent: dielectric constant > 15 • nonpolar solvent: dielectric constant < 15 9-6 Protic Solvents Structure H2 O HCOOH Dielectric Constant (25°C) 79 59 Methanol CH3 OH 33 Ethanol CH3 CH2 OH 24 Acetic acid CH3 COOH 6 Solvent Water Formic acid 9-7 Aprotic Solvents Dielectric Constant Solvent Polar Dimethyl sulfoxide (DMSO) Structure ( CH 3 ) 2 S=O 48.9 Acetonitrile CH 3 C N 37.5 N,N-Dimethylformamide (DMF) ( CH 3 ) 2 NCHO 36.7 Acetone ( CH 3 ) 2 C=O 20.7 Nonpolar Dichloromethane Diethyl ether CH2 Cl2 CH3 CH 2 OCH2 CH3 Toluene Hexane C6 H5 CH3 CH3 ( CH 2 ) 4 CH3 9.1 4.3 2.3 1.9 9-8 Mechanisms Chemists propose two limiting mechanisms for nucleophilic substitution • a fundamental difference between them is the timing of bond-breaking and bond-forming steps At one extreme, the two processes take place simultaneously; designated SN2 • S = substitution • N = nucleophilic • 2 = bimolecular (two species are involved in the ratedetermining step) 9-9 Mechanism - SN2 • both reactants are involved in the transition state of the rate-determining step H H + : Br : C : HO : Br : : C : HO : : Br : : C : : + : : : - HO: H - - H H H H H H Transition state with simultaneous bond breaking and bond forming 9-10 Mechanism - SN2 9-11 Mechanism - SN1 Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins This mechanism is designated SN1 where • S = substitution • N = nucleophilic • 1 = unimolecular (only one species is involved in the rate-determining step) 9-12 Mechanism - SN1 • Step 1: ionization of the C-X bond gives a carbocation intermediate H3 C C H3 C H3 C Br slow, rate determining CH3 C+ + Br H3 C CH3 A carbocation intermediate; its shape is trigonal planar 9-13 Mechanism - SN1 • Step 2: reaction of the carbocation (an electrophile) with methanol (a nucleophile) gives an oxonium ion CH3 + : C+ : OCH3 fast H H3 C CH3 Electrophile CH 3 H3 C :O H Nucleophile + C CH3 H3 C CH 3 CH 3 C O: H 3C H 3C H Oxonium ions • Step 3: proton transfer completes the reaction CH3 H + O: + :O : CH3 H fast H3 C C H3 C H3 C H CH3 + : + O H O: CH3 : H3 C C H3 C H3 C 9-14 Mechanism - SN1 9-15 Evidence of SN reactions 1. What is relationship between the rate of an SN reaction and: • • • • the structure of Nu? the structure of RLv? the structure of the leaving group? the solvent? 2. What is the stereochemical outcome if the leaving group is displaced from a chiral center? 3. Under what conditions are skeletal rearrangements observed? 9-16 Kinetics For an SN1 reaction • reaction occurs in two steps • the reaction leading to formation transition state for the carbocation intermediate involves only the haloalkane and not the nucleophile • the result is a first-order reaction CH3 + CH3 OH CH3 CBr CH3 2-Bromo-2Methanol methylpropane Rate = - d[ (CH3 ) 3 CBr] dt CH3 CH3 COCH3 + HBr CH3 2-Methoxy-2methylpropane = k[( CH3 ) 3 CBr] 9-17 Kinetics For an SN2 reaction, • reaction occurs in one step • the reaction leading to the transition state involves the haloalkane and the nucleophile • the result is a second-order reaction; first order in haloalkane and first order in nucleophile CH3 Br + N a+ OHBromomethane rate = d[ CH 3 Br] dt CH3 OH + Na+ BrMethanol - = k[ CH3 Br] [ OH ] 9-18 Nucleophilicity Nucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity 9-19 Nucleophilicity Effectiveness Nucleophile - Good Moderate Poor - Br , I CH3 S , RS HO , CH3 O , RO CN-, N3 Cl-, FCH3 COO , RCOO CH3 SH, RSH, R2 S NH3 , RNH2 , R2 NH, R3 N H2 O CH3 OH, ROH CH3 COOH, RCOOH 9-20 Nucleophilicity Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents Solvent How Increasing Nucleophilicity Polar aprotic I - < Br - < Cl- < F- Polar protic F - < Cl - < Br - < I - do we account for these differences? 9-21 Nucleophilicity A guiding principle is the freer the nucleophile, the greater its nucleophilicity Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF) • are very effective in solvating cations, but not nearly so effective in solvating anions. • because anions are only poorly solvated, they participate readily in SN reactions, and • nucleophilicity parallels basicity: F- > Cl- > Br- > I- 9-22 Nucleophilicity Polar protic solvents (e.g., water, methanol) • anions are highly solvated by hydrogen bonding with the solvent • the more concentrated the negative charge of the anion, the more tightly it is held in a solvent shell • the nucleophile must be at least partially removed from its solvent shell to participate in SN reactions • because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F- 9-23 Nucleophilicity Generalization • within a row of the Periodic Table, nucleophilicity increases from left to right; that is, it increases with basicity Period Increasing Nucleophilicity Period 2 F- < Period 3 Cl - OH- < < SH- < NH 2 - < CH3 - PH2 - 9-24 Nucleophilicity Generalization • in a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents; this trend parallels the basicity of the nucleophile Increasing Nucleophilicity - H2 O < OH ROH < RO NH 3 < NH 2 RSH < RS - - 9-25 Nucleophilicity Generalization • when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity Nucleophile - RCOO Carboxylate ion - HO Hydroxide ion - RO Alkoxide ion Increasing Nucleophilicity Conjugate acid pKa RCOOH 4-5 HOH 15.7 Increasing Acidity ROH 16-18 9-26 Stereochemistry For an SN1 reaction at a chiral center, the R and S enantiomers are formed in equal amounts, and the product is a racemic mixture C Cl H Cl R Enantiomer - Cl - C+ CH 3 OH -H + H Cl Planar carbocation (achiral) + CH 3 O C C OCH 3 H H Cl Cl S Enantiomer R Enantiomer A racemic mixture 9-27 Stereochemistry For SN1 reactions at a chiral center • examples of complete racemization have been observed, but • partial racemization with a slight excess of inversion is more common Approach of the nucleophile from this side is less hindered R1 C+ H R2 Cl- Approach of the nucleophile from this side is partially blocked by leaving group, which remains associated with the carbocation as an ion pair 9-28 Stereochemistry For SN2 reactions at a chiral center, there is inversion of configuration at the chiral center Experiment of Hughes and Ingold 131 I + 131 2-Iodooctane I - SN 2 acetone I + I - 9-29 Hughes-Ingold Expt • the reaction is 2nd order, therefore, SN2 • the rate of racemization of enantiomerically pure 2iodooctane is twice the rate of incorporation of I-131 C6 H1 3 131 - I: + C H H3 C I S N2 acetone (S)-2-Iodooctane C6 H1 3 131 I + C I H CH3 (R)-2-Iodooctane 9-30 Structure of RX SN1 reactions: governed by electronic factors • the relative stabilities of carbocation intermediates SN2 reactions: governed by steric factors • the relative ease of approach of a nucleophile to the reaction site Governed by electronic factors SN 1 Carbocation stability R3 CX (3°) R2 CHX (2°) RCH2 X CH3 X (1°) (methyl) Access to the site of reaction SN 2 Governed by steric factors 9-31 Effect of -Branching Br Br Br Br Alkyl Bromide -Branches 0 1 2 3 1.0 4.1x 10-1 -3 1.2 x 10 1.2x 10-5 Relative Rate 9-32 Effect of -Branching CH3 CH3 CH2 Br CH3 CCH2 Br CH3 free access blocked access Bromoethane (Ethyl bromide) 1-Bromo-2,2-dimethylpropane (Neopentyl bromide) 9-33 Allylic Halides Allylic cations are stabilized by resonance delocalization of the positive charge • a 1° allylic cation is about as stable as a 2° alkyl cation + CH2 = CH- CH 2 + CH2 -CH = CH 2 Allyl cation (a hybrid of two equivalent contributing structures) 9-34 Allylic Cations • 2° & 3° allylic cations are even more stable + + CH2 =CH-CH-CH3 A 2° allylic carbocation CH2 =CH-C-CH3 CH3 A 3° allylic carbocation • as also are benzylic cations CH2 + C6 H5 -CH2 + Benzyl cation (a benzylic carbocation) The benzyl cation is also written in this abbreviated form • adding these carbocations to those from Section 6.3 methyl < 1° alkyl < 2° alkyl 1° allylic < 1° benzylic 3° alkyl 2° allylic < 2° benzylic 3° allylic 3° benzylic Increasing stability of carbocations 9-35 The Leaving Group The more stable the anion, the better the leaving ability • the most stable anions are the conjugate bases of strong acids rarely function as leaving groups Reactivity as a leaving group - - - O - - - - I > Br > Cl > H2 O >> F > CH3 CO > HO > CH3 O > NH2 - Stability of anion; strength of conjugate acid 9-36 The Solvent - SN2 The most common type of SN2 reaction involves a negative Nu and a negative leaving group negatively charged nucleophile - Nu: + C Lv negative charge dispersed in the transition state Nu C Lv negatively charged leaving group Nu C + Lv Transition state • the weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of SN2 9-37 The Solvent - SN2 Br + N3 Solvent Type - SN 2 solvent Solvent CH3 C N polar aprotic ( CH ) NCHO 3 2 ( CH3 ) 2 S= O polar protic H2 O CH3 OH N3 + Br - k(solvent) k(methanol) 5000 2800 1300 7 1 9-38 The Solvent - SN1 SN1 reactions involve creation and separation of unlike charge in the transition state of the ratedetermining step Rate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cation Polar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions 9-39 The Solvent - SN1 CH3 CH3 CCl + ROH solvolysis CH3 CH3 CH3 COR + HCl CH3 k(solvent) Solvent water k(ethano l) 100,000 80% water: 20% ethanol 14,000 40% water: 60% ethanol ethanol 100 1 9-40 Rearrangements in SN1 Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one + CH3 OH CH3 OH Cl 2-Chloro-3phenylbutane OCH3 + + CH3 OH + Cl H 2-Methoxy-2-phenylbutane 9-41 Rearrangements in SN1 Mechanism of a carbocation rearrangement (1) + Cl + : Cl A 2° carbocation (2) + H H + A 3° benzylic carbocation H (3) + + : O-CH3 + H O CH3 An oxonium ion 9-42 Summary of SN1 & SN2 Type of Alkyl Halide Methyl SN 2 SN 2 is favored. SN 1 does not occur. The methyl cation is so unstable, it is never observed in solution. SN 2 is favored. SN 1 rarely occurs. Primary cations are so unstable, that they are never observed in solution. SN 2 is favored in aprotic solvents with good nucleophiles. SN 1 is favored in protic solvents with poor nucleophiles. Carbocation rearrangements may occur. CH3 X Primary RCH2 X Secondary R2 CHX Tertiary R3 CX SN 1 SN 2 does not occur because SN 1 is favored because of the ease of of steric hindrance around formation of tertiary carbocations. the reaction center. Substitution Inversion of configuration. at a The nucleophile attacks stereocenter the stereocenter from the side opposite the leaving group. Racemization is favored. The carbocation intermediate is planar, and attack of the nucleophile occurs with equal probability from either side. There is often some net inversion of configuration. 9-43 SN1/SN2 Problems • Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product Cl OCH3 OH + + CH3 OH/ H2 O + HCl (R)-2-Chlorobutane • Problem 2: predict the mechanism of this reaction Br + N a+ CN- DMSO CN + N a+ Br - 9-44 SN1/SN2 Problems • Problem 3: predict the mechanism of this reaction and the configuration of product Br SCH3 + CH3 S- Na+ acetone + Na+ Br- (R)-2- Bromobutane • Problem 4: predict the mechanism of this reaction and the configuration of the product O Br + CH3 COH acetic acid O OCCH3 + HBr (R)-3-Bromocyclohexene 9-45 SN1/SN2 Problems • Problem 5: predict the mechanism of this reaction Br + ( CH3 ) 3 P toluene + P( CH3 ) 3 Br - 9-46 -Elimination -Elimination: a reaction in which a molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons H C C X A haloalkane + CH3 CH2 O-Na+ CH3 CH2 OH Base C C + CH3 CH2 OH + Na+ X - An alkene 9-47 -Elimination rule: the major product of a -elimination is the more stable (the more highly substituted) alkene Zaitsev Br 2-Bromo-2methylbutane Br CH 3 CH2 O - Na + CH3 CH2 OH + 2-Methyl-2-butene 2-Methyl-1-butene (major product) CH 3 O - Na + CH3 OH 1-Bromo-1-methylcyclopentane + 1-MethylMethylenecyclopentene cyclopentane (major product) 9-48 -Elimination are two limiting mechanisms for elimination reactions E1 mechanism: at one extreme, breaking of the R-Lv There bond to give a carbocation is complete before reaction with base to break the C-H bond • only R-Lv is involved in the rate-determining step E2 mechanism: at the other extreme, breaking of the R- Lv and C-H bonds is concerted • both R-Lv and base are involved in the rate-determining step 9-49 E1 Mechanism • ionization of C-Lv gives a carbocation intermediate CH3 CH3 -C-CH3 slow, rate determining Br CH3 CH3 -C-CH3 + + Br (A carbocation intermediate) • proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene H H3 C CH3 O: + H-CH2 -C-CH3 + fast H + CH3 O H + CH2 =C-CH3 H3 C 9-50 E1 Mechanism 9-51 E2 Mechanism 9-52 Kinetics of E1 and E2 E1 mechanism • reaction occurs in two steps • the rate-determining step is carbocation formation • the reaction is 1st order in RLv and zero order is base Rate = E2 d[RLv] dt = k[ RLv] mechanism • reaction occurs in one step • reaction is 2nd order; first order in RLv and 1st order in base Rate = d[RLv] dt = k[ RLv][ Base] 9-53 Regioselectivity of E1/E2 E1: major product is the more stable alkene E2: with strong base, the major product is the more stable (more substituted) alkene • double bond character is highly developed in the transition state • thus, the transition state of lowest energy is that leading to the most stable (the most highly substituted) alkene E2: with a strong, sterically hindered base such as tert-butoxide, the major product is often the less stable (less substituted) alkene 9-54 Stereoselectivity of E2 E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar CH3 O: - CH3 O H H C C Lv -H and -Lv are anti and coplanar (dihedral angle 180°) C C Lv 9-55 Stereochemistry of E2 Consider E2 of these stereoisomers - + CH3 O Na Cl cis-1-Chloro-2isopropylcyclohexane CH3 OH 1-Isopropylcyclohexene (major product) - CH3 O Na Cl trans-1-Chloro-2isopropylcyclohexane + (R)-3-Isopropylcyclohexene + CH3 OH (R)-3-Isopropylcyclohexene 9-56 Stereochemistry of E2 • in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial - CH3 O: H 2 H 6 H E2 + CH3 OH + :Cl H 1 Cl 1-Isopropylcyclohexene 9-57 Stereochemistry of E2 • in the more stable chair of the trans isomer, there is no H anti and coplanar with Lv, but there is one in the less stable chair H H 6 H Cl 2 Cl H 6 1 2 1 H H H More stable chair (no H is anti and coplanar to Cl) H Less stable chair (H on carbon 6 is anti and coplanar to Cl) 9-58 Stereochemistry of E2 • it is only the less stable chair conformation of this isomer that can undergo an E2 reaction Cl H CH3 O: - 6 H 2 1 H E2 + CH3 OH + Cl H (R)-3-Isopropylcyclohexene 9-59 Stereochemistry of E2 Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E alkene Br Br C6 H5 CH-CHC6 H5 meso-1,2-Dibromo1,2-diphenylethane C6 H5 - CH3 O Na CH3 OH + C6 H5 C C H Br (E)-1-Bromo-1,2diphenylethylene 9-60 Summary of E2 vs E1 Alkyl halide Primary E1 E2 E2 is favored. RCH2 X E1 does not occur. Primary carbocations are so unstable, they are never observed in solution. Secondary R2 CHX Main reaction with weak bases such as H2O, ROH. Main reaction with strong bases such as OH - and OR-. Tertiary R3 CX Main reaction with weak bases such as H2O, ROH. Main reaction with strong bases such as OH - and OR-. 9-61 SN vs E nucleophiles are also strong bases (OHand RO-) and SN and E reactions often compete The ratio of SN/E products depends on the relative rates of the two reactions Many nucleophilic substitution H C C Lv + H C C Nu + Lv Nu-elimination C C + H-Nu + Lv 9-62 SN vs E Halide Reaction Comments Methyl CH3 X SN2 SN 1 reactions of methyl halides are never observed. The methyl cation is so unstable that it is never formed in solution. Primary RCH2 X SN 2 The main reaction with good nucleophiles/weak bases such as I- and CH3 COO-. E2 The main reaction with strong, bulky bases such as potassium tert-butoxide. Primary cations are never observeded in solution and, therefore, SN1 and E1 reactions of primary halides are never observed. 9-63 SN vs E (cont’d) Secondary SN 2 R2 CHX Tertiary R3 CX The main reaction with bases/nucleophiles where pK a of the conjugate acid is 11 or less, as for example I - and CH 3COO -. E2 The main reaction with bases/nucleophiles where the pK a of the conjugate acid is 11 or greater, as for example OH - and CH3CH2O -. SN 1/E1 Common in reactions with weak nucleophiles in polar protic solvents, such as water, methanol, and ethanol. E2 M ain reaction with strong bases such as HO - and RO-. SN 1/E1 M ain reactions with poor nucleophiles/weak bases. SN 2 reactions of tertiary halides are never observed because of the extreme crowding around the 3° carbon. 9-64 Neighboring Groups In an SN2 reaction, departure of the leaving group is assisted by Nu; in an SN1 reaction, it is not These two types of reactions are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st order But some substitution reactions are 1st order and yet involve two successive SN2 reactions 9-65 Mustard Gases Mustard gases • contain either S-C-C-X or N-C-C-X N S Cl Cl Bis(2-chloroethyl)sulfide (a sulfur mustard gas) Cl Cl Bis(2-chloroethyl)methylamine (a nitrogen mustard gas) • what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile Cl S Cl + 2 H2 O HO S OH + 2 HCl 9-66 Mustard Gases • the reason is neighboring group participation by the adjacent heteroatom : slow, rate determining S Cl S Cl + : O-H H an internal SN 2 reaction fast a second S N2 reaction Cl S + Cl A cyclic sulfonium ion : + Cl + S Cl H +O H • proton transfer to solvent completes the reaction 9-67 Phase-Transfer Catalysis A substance that transfers ions from an aqueous phase to an organic phase An effective phase-transfer catalyst must have sufficient • hydrophilic character to dissolve in water and form an ion pair with the ion to be transported • hydrophobic character to dissolve in the organic phase and transport the ion into it The following salt is an effective phase-transfer catalysts for the transport of anions ( CH3 CH2 CH2 CH2 ) 4 N + Cl Tetrabutylammonium chloride (Bu4N + Cl- ) 9-68 Phase-Transfer Catalysis 9-69 Nucleophilic Substitution and -Elimination End Chapter 9 9-70