9-1 Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson William H. Brown Christopher S. Foote Brent L. Iverson

9-2 Nucleophilic Substitution and  -Elimination  Chapter 8 Chapter 9

9-3 Nucleophilic Substitution  Nucleophilic substitution:  Nucleophilic substitution: any reaction in which one nucleophile substitutes for another at a tetravalent carbon  Nucleophile:  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

9-4 Nucleophilic Substitution  Some nucleophilic substitution reactions

9-5 Solvents  Protic solvent:  Protic solvent: a solvent that is a hydrogen bond donor the most common protic solvents contain -OH groups  Aprotic solvent:  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

9-6 Dielectric Constant  Solvents are classified as polar and nonpolar the most common measure of solvent polarity is dielectric constant  Dielectric constant:  Dielectric constant: a measure of a solvent’s ability to insulate opposite charges from one another 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

9-7 Protic Solvents

9-8 Aprotic Solvents

9-9 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 S N 2 S = substitution N = nucleophilic 2 = bimolecular (two species are involved in the rate- determining step)

9-10 Mechanism - S N 2 both reactants are involved in the transition state of the rate-determining step

9-11 Mechanism - S N 2

9-12 Mechanism - S N 1  Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins  This mechanism is designated S N 1 where S = substitution N = nucleophilic 1 = unimolecular (only one species is involved in the rate-determining step)

9-13 Mechanism - S N 1 Step 1: ionization of the C-X bond gives a carbocation intermediate

9-14 Mechanism - S N 1 Step 2: reaction of the carbocation (an electrophile) with methanol (a nucleophile) gives an oxonium ion Step 3: proton transfer completes the reaction

9-15 Mechanism - S N 1

9-16 Evidence of S N reactions 1. What is relationship between the rate of an S N 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?

9-17 Kinetics  For an S N 1 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

9-18 Kinetics  For an S N 2 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

9-19 Nucleophilicity  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:  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

9-20 Nucleophilicity

9-21 Nucleophilicity  Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents  How do we account for these differences? Increasing Nucleophilicity Solvent Polar aprotic Polar protic F - < Cl - < Br - < I - I - < Br - < Cl - < F -

9-22 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 S N reactions, and nucleophilicity parallels basicity: F - > Cl - > Br - > I -

9-23 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 S N reactions because F - is most tightly solvated and I - the least, nucleophilicity is I - > Br - > Cl - > F -

9-24 Nucleophilicity  Generalization within a row of the Periodic Table, nucleophilicity increases from left to right; that is, it increases with basicity Increasing NucleophilicityPeriod Period 2 Period 3 F - < OH - < NH 2 - < CH 3 - Cl - < SH - < PH 2 -

9-25 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 ROH < RO - H 2 O < OH - NH 3 < NH 2 - RSH < RS -

9-26 Nucleophilicity  Generalization when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity

9-27 Stereochemistry  For an S N 1 reaction at a chiral center, the R and S enantiomers are formed in equal amounts, and the product is a racemic mixture C H Cl Cl -Cl - C+ H Cl CH 3 OH -H + CH 3 OC H Cl Cl COCH 3 H R EnantiomerS Enantiomer + R Enantiomer A racemic mixture Planar carbocation (achiral)

9-28 Stereochemistry  For S N 1 reactions at a chiral center examples of complete racemization have been observed, but partial racemization with a slight excess of inversion is more common

9-29 Stereochemistry  For S N 2 reactions at a chiral center, there is inversion of configuration at the chiral center  Experiment of Hughes and Ingold

9-30 Hughes-Ingold Expt the reaction is 2nd order, therefore, S N 2 the rate of racemization of enantiomerically pure 2- iodooctane is twice the rate of incorporation of I-131

9-31 Structure of RX  S N 1 reactions: governed by electronic factors the relative stabilities of carbocation intermediates  S N 2 reactions: governed by steric factors the relative ease of approach of a nucleophile to the reaction site Governed by electronic factors Governed by steric factors S N 1 S N 2 R 3 CXR 2 CHXRCH 2 XCH 3 X Access to the site of reaction (3°) (methyl) (2°)(1°) Carbocation stability

9-32 Effect of  -Branching 1.2 x x Relative Rate Alkyl Bromide  -Branches x 10 Br Br Br Br  

9-33 Effect of  -Branching Bromoethane (Ethyl bromide) 1-Bromo-2,2-dimethylpropane (Neopentyl bromide)

9-34 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 ++ Allyl cation (a hybrid of two equivalent contributing structures) CH 2 =CH-CH 2 CH 2 -CH=CH 2

9-35 Allylic Cations 2° & 3° allylic cations are even more stable as also are benzylic cations adding these carbocations to those from Section 6.3

9-36 The Leaving Group  The more stable the anion, the better the leaving ability the most stable anions are the conjugate bases of strong acids

9-37 The Solvent - S N 2  The most common type of S N 2 reaction involves a negative Nu and a negative leaving group the weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of S N 2

9-38 The Solvent - S N 2 Br N 3 - CH 3 CN CH 3 OH H 2 O (CH 3 ) 2 S=O (CH 3 ) 2 NCHO N 3 Br - Solvent Type polar aprotic polar protic k (methanol) k (solvent) Solvent + solvent S N 2 +

9-39 The Solvent - S N 1  S N 1 reactions involve creation and separation of unlike charge in the transition state of the rate- determining 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 S N 1 reactions

9-40 The Solvent - S N 1

9-41 Rearrangements in S N 1  Rearrangements are common in S N 1 reactions if the initial carbocation can rearrange to a more stable one

9-42 Rearrangements in S N 1  Mechanism of a carbocation rearrangement

9-43 Summary of S N 1 & S N 2

9-44 S N 1/S N 2 Problems Problem 1:Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product Problem 2:Problem 2: predict the mechanism of this reaction

9-45 S N 1/S N 2 Problems Problem 3:Problem 3: predict the mechanism of this reaction and the configuration of product Problem 4:Problem 4: predict the mechanism of this reaction and the configuration of the product

9-46 S N 1/S N 2 Problems Problem 5:Problem 5: predict the mechanism of this reaction

9-47  -Elimination   -Elimination:   -Elimination: a reaction in which a molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons

9-48  -Elimination  Zaitsev rule:  Zaitsev rule: the major product of a  -elimination is the more stable (the more highly substituted) alkene 2-Methyl-2-butene (major product) CH 3 CH 2 O - Na + CH 3 CH 2 OH 2-Bromo-2- methylbutane 2-Methyl-1-butene Br Methyl- cyclopentene (major product) CH 3 O - Na + CH 3 OH 1-Bromo-1-methyl- cyclopentane Br Methylene- cyclopentane

9-49  -Elimination  There are two limiting mechanisms for  - elimination reactions  E1 mechanism:  E1 mechanism: at one extreme, breaking of the R-Lv 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:  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

9-50 E1 Mechanism ionization of C-Lv gives a carbocation intermediate proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene

9-51 E1 Mechanism

9-52 E2 Mechanism

9-53 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  E2 mechanism reaction occurs in one step reaction is 2nd order; first order in RLv and 1st order in base

9-54 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

9-55 Stereoselectivity of E2  E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar

9-56 Stereochemistry of E2  Consider E2 of these stereoisomers

9-57 Stereochemistry of E2 in the more stable chair of the cis isomer, the larger isopropyl is equatorial and chlorine is axial

9-58 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

9-59 Stereochemistry of E2 it is only the less stable chair conformation of this isomer that can undergo an E2 reaction

9-60 Stereochemistry of E2 Problem: Problem: account for the fact that E2 reaction of the meso-dibromide gives only the E alkene

9-61 Summary of E2 vs E1

9-62 S N vs E  Many nucleophiles are also strong bases (OH - and RO - ) and S N and E reactions often compete  The ratio of S N /E products depends on the relative rates of the two reactions

9-63 S N vs E

9-64 S N vs E (cont’d) The main reaction with bases/nucleophiles where the R 3 CX pK a of the conjugate acid is 11 or less, as for example I - and CH 3 COO -. R 2 CHX Main reaction with strong bases such as HO - and RO -. Main reactions with poor nucleophiles/weak bases. The main reaction with bases/nucleophiles where E2 S N 2 S N 2 reactions of tertiary halides are never observed S N 1/E1 Secondary Tertiary because of the extreme crowding around the 3° carbon. S N 1/E1 Common in reactions with weak nucleophiles in polar protic solvents, such as water, methanol, and ethanol. pK a of the conjugate acid is 11 or greater, as for example OH - and CH 3 CH 2 O -.

9-65 Neighboring Groups  In an S N 2 reaction, departure of the leaving group is assisted by Nu; in an S N 1 reaction, it is not  These two types of reactions are distinguished by their order of reaction; S N 2 reactions are 2nd order, and S N 1 reactions are 1st order  But some substitution reactions are 1st order and yet involve two successive S N 2 reactions

9-66 Mustard Gases  Mustard gases contain either S-C-C-X or N-C-C-X what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile Bis(2-chloroethyl)sulfide (a sulfur mustard gas) Bis(2-chloroethyl)methylamine (a nitrogen mustard gas)

9-67 Mustard Gases the reason is neighboring group participation by the adjacent heteroatom proton transfer to solvent completes the reaction

9-68 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 (CH 3 CH 2 CH 2 CH 2 ) 4 N + Cl - Tetrabutylammonium chloride (Bu 4 N + Cl - )

9-69 Phase-Transfer Catalysis

9-70 Nucleophilic Substitution and  -Elimination End Chapter 9