Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,9-,70,Organic Chemistry,William H. Brown,Christopher S. Foote,Brent L. Iverson,Organic ChemistryWilliam H. Br,Nucleophilic Substitution and,-Elimination,Chapter 8,Chapter 9,Nucleophilic Substitution and,Nucleophilic Substitution,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,Nucleophilic Substitution,Nucleophilic Substitution,Some nucleophilic substitution reactions,Nucleophilic SubstitutionSome,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,SolventsProtic solvent: a solv,Dielectric Constant,Solvents are classified as polar and nonpolar,the most common measure of solvent polarity is dielectric constant,Dielectric constant:,a measure of a solvents 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,Dielectric ConstantSolvents ar,Protic Solvents,Protic Solvents,Aprotic Solvents,Aprotic Solvents,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),MechanismsChemists propose two,Mechanism - S,N,2,both reactants are involved in the transition state of the rate-determining step,Mechanism - SN2both reactants,Mechanism - S,N,2,Mechanism - SN2,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),Mechanism - SN1Bond breaking b,Mechanism - S,N,1,Step 1: ionization of the C-X bond gives a carbocation intermediate,Mechanism - SN1Step 1: ionizat,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,Mechanism - SN1Step 2: reactio,Mechanism - S,N,1,Mechanism - SN1,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?,Evidence of SN reactions1. Wha,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,KineticsFor an SN1 reaction,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,KineticsFor an SN2 reaction,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,NucleophilicityNucleophilicity,Nucleophilicity,Nucleophilicity,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,-,C,l,-,B,r,-,I,-,I,-,B,r,-,C,l,-, Cl,-, Br,-, I,-,NucleophilicityA guiding princ,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,-,NucleophilicityPolar protic so,Nucleophilicity,Generalization,within a row of the Periodic Table, nucleophilicity increases from left to right; that is, it increases with basicity,Increasing Nucleophilicity,P,e,r,i,o,d,P,e,r,i,o,d,2,P,e,r,i,o,d,3,F,-,O,H,-,N,H,2,-,C,H,3,-,C,l,-,S,H,-,P,H,2,-,NucleophilicityGeneralizationI,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,R,O,H,R,O,-,H,2,O,O,H,-,N,H,3,N,H,2,-,R,S,H,R,S,-,NucleophilicityGeneralizationI,Nucleophilicity,Generalization,when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity,NucleophilicityGeneralization,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,C,l,C,l,-,C,l,-,C,+,H,C,l,C,H,3,O,H,-,H,+,C,H,3,O,C,H,C,l,C,l,C,O,C,H,3,H,R Enantiomer,S Enantiomer,+,R Enantiomer,A racemic mixture,Planar carbocation,(achiral),StereochemistryFor an SN1 reac,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,StereochemistryFor SN1 reactio,Stereochemistry,For S,N,2 reactions at a chiral center, there is inversion of configuration at the chiral center,Experiment of Hughes and Ingold,StereochemistryFor SN2 reactio,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,Hughes-Ingold Exptthe reaction,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,C,X,R,2,C,H,X,R,C,H,2,X,C,H,3,X,Access to the site of reaction,(3),(methyl),(2,),(1),Carbocation stability,Structure of RXSN1 reactions:,Effect of,-Branching,1.2,x 10,-5,1.2 x 10,-3,Relative Rate,Alkyl Bromide,b,-Branches,0,1,2,3,1.0,4.1,x 10,-1,B,r,B,r,B,r,B,r,b,b,b,b,Effect of -Branching1.2 x 10-,Effect of,-Branching,Bromoethane,(Ethyl bromide),1-Bromo-2,2-dimethylpropane,(Neopentyl bromide),Effect of -BranchingBromoetha,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),C,H,2,=,C,H,-,C,H,2,C,H,2,-,C,H,=,C,H,2,Allylic HalidesAllylic cations,Allylic Cations,2 & 3 allylic cations are even more stable,as also are benzylic cations,adding these carbocations to those from Section 6.3,Allylic Cations2 & 3 allylic,The Leaving Group,The more stable the anion, the better the leaving ability,the most stable anions are the conjugate bases of strong acids,The Leaving GroupThe more stab,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,The Solvent - SN2The most comm,The Solvent - S,N,2,B,r,N,3,-,C,H,3,C,N,C,H,3,O,H,H,2,O,(,C,H,3,),2,S,=,O,(,C,H,3,),2,N,C,H,O,N,3,B,r,-,Solvent,Type,polar aprotic,polar protic,5000,2800,1300,7,1,k,(methanol),k,(solvent),Solvent,+,solvent,S,N,2,+,The Solvent - SN2BrN3-CH3CNCH3,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,The Solvent - SN1SN1 reactions,The Solvent - S,N,1,The Solvent - SN1,Rearrangements in S,N,1,Rearrangements are common in S,N,1 reactions if the initial carbocation can rearrange to a more stable one,Rearrangements in SN1Rearrange,Rearrangements in S,N,1,Mechanism of a carbocation rearrangement,Rearrangements in SN1Mechanism,Summary of S,N,1 & S,N,2,Summary of SN1 & SN2,S,N,1/S,N,2 Problems,Problem 1:,predict the mechanism for this reaction, and the stereochemistry of each product,Problem 2:,predict the mechanism of this reaction,SN1/SN2 ProblemsProblem 1: pre,S,N,1/S,N,2 Problems,Problem 3:,predict the mechanism of this reaction and the configuration of product,Problem 4:,predict the mechanism of this reaction and the configuration of the product,SN1/SN2 ProblemsProblem 3: pre,S,N,1/S,N,2 Problems,Problem 5:,predict the mechanism of this reaction,SN1/SN2 ProblemsProblem 5: pre,-Elimination,-Elimination:,a reaction in which a molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons,-Elimination-Elimination: a,-Elimination,Zaitsev rule:,the major product of a,-elimination is the more stable (the more highly substituted) alkene,2-Methyl-2-butene,(major product),C,H,3,C,H,2,O,-,N,a,+,C,H,3,C,H,2,O,H,2-Bromo-2-,methylbutane,2-Methyl-1-butene,B,r,+,+,1-Methyl-,cyclopentene,(major product),C,H,3,O,-,N,a,+,C,H,3,O,H,1-Bromo-1-methyl-,cyclopentane,B,r,Methylene-,cyclopentane,-EliminationZaitsev rule: the,-Elimination,There are two limiting mechanisms for,-elimination reactions,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:,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,-EliminationThere are two lim,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,E1 Mechanismionization of C-Lv,E1 Mechanism,E1 Mechanism,E2 Mechanism,E2 Mechanism,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,Kinetics of E1 and E2E1 mechan,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,Regioselectivity of E1/E2E1: m,Stereoselectivity of E2,E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar,Stereoselectivity of E2E2 is m,Stereochemistry of E2,Consider E2 of these stereoisomers,Stereochemistry of E2Consider,Stereochemistry of E2,in the more stable chair of the,cis,isomer, the larger isopropyl is equatorial and chlorine is axial,Stereochemistry of E2in the mo,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,Stereochemistry of E2in the mo,Stereochemistry of E2,it is only the less stable chair conformation of this isomer that can undergo an E2 reaction,Stereochemistry of E2it is onl,Stereochemistry of E2,Problem:,account for the fact that E2 reaction of the meso-dibromide gives only the,E,alkene,Stereochemistry of E2Problem:,Summary of E2 vs E1,Summary of E2 vs E1,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,SN vs EMany nucleophiles are a,S,N,vs E,SN vs E,S,N,vs E (contd),T,h,e,m,a,i,n,r,e,a,c,t,i,o,n,w,i,t,h,b,a,s,e,s,/,n,u,c,l,e,o,p,h,i,l,e,s,w,h,e,r,e,t,h,e,R,3,C,X,p,K,a,o,f,t,h,e,c,o,n,j,u,g,a,t,e,a,c,i,d,i,s,1,1,o,r,l,e,s,s,a,s,f,o,r,e,x,a,m,p,l,e,I,-,a,n,d,C,H,3,C,O,O,-,.,R,2,C,H,X,M,a,i,n,r,e,a,c,t,i,o,n,w,i,t,h,s,t,r,o,n,g,b,a,s,e,s,s,u,c,h,a,s,H,O,-,a,n,d,R,O,-,.,M,a,i,n,r,e,a,c,t,i,o,n,s,w,i,t,h,p,o,o,r,n,u,c,l,e,o,p,h,i,l,e,s,/,w,e,a,k,b,a,s,e,s,.,The main reaction with bases/nucleophiles where,E2,S,N,2,E2,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,-,.,SN vs E (contd)The main react,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,Neighboring GroupsIn an SN2 re,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),C,l,S,C,l,C,l,N,C,l,Mustard GasesMustard gases Bis,Mustard Gases,the reason is neighboring group participation by the adjacent heteroatom,proton transfer to solvent completes the reaction,Mustard Gasesthe reason is nei,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,(,C,H,3,C,H,2,C,H,2,C,H,2,),4,N,+,C,l,-,T,etrabutylammonium chloride,(Bu,4,N,+,Cl,-,),Phase-Transfer CatalysisA subs,Phase-Transfer Catalysis,Phase-Transfer Catalysis,Nucleophilic Substitution and,-Elimination,End Chapter 9,Nucleophilic Substitution and,