Lecture 7B: Substitution and Elimination Reactions of Organohalides

reactivity of alkyl halides

• alkyl halides are prone to undergo nucleophilic substitutions (SN) and elimination reactions (E)

• alkenyl halides, aryl halides, and allylic halides have a different reactivity and do not undergo SN or E reactions

nucleophilic substitution reaction mechanism

• the nucleophile donates an electron pair to the substrate

  • the nucleophile uses its electron pair to form a new covalent bond with the substrate C

• the Leaving Group gains the pair of electrons originally bonded in the substrate

  • the bond between C and Leaving Group breaks, giving both electrons from the bond to the Leaving Group

definition of terms

• kinetics - refers to the concentration of the reactants and the rate at which the reaction occurs

timing of the bond breaking and bond making process

• types of mechanism

  • 1st type: SN2 (concerted mechanism)

  • 2nd type: SN1 (stepwise mechanism

SN2 reactions

• a reaction in which the rate is linearly dependent on the concentration of the reactants

• SN2 reaction if short for substitution, nucleophilic, and bimolecular

• reaction rate formula:

structure of SN2 reactions

• stereochemistry is inversion of configuration

• steric effects on SN2 reactions

  • partial bond is formed between the incoming nucleophile and the alkyl halide carbon atom

  • bond formation is difficult with the nucleophile

  • the substrate possesses a higher energy than a less hindered substrate

order of reactivity

• the more alkyl groups connected to the reacting carbon, the slower the reaction

the nucleophile in SN2 reactions

• neutral or negatively charged lewis base

• negatively charged nucleophile yields a neutral product

• neutral nucleophile yields a positively charged product

• based on the reactions of nucleophilic substances with bromoethane, some reactants seem to be more nucleophilic than others

• nucleophilicity is based on the concentration of the substrate, the solvent, and the reactant

• trends observed in nucleophiles

  • nucleophilicity roughly parallels basicity

  • nucleophilicity increases with downward progression in the periodic table

  • nucleophiles with a negative charge are generally more reaction that those that are neutral

the leaving group in SN2 reactions

• the leaving group is the group that is displaced by the incoming nucleophile in the SN2 reaction

• leaving groups that provide optimal stability to the negative charge in the transition state are considered the best

• weak bases are good leaving groups, and strong bases are poor leaving groups

• an SN2 reaction with an alcohol requires conversion to an alkyl chloride or an alkyl bromide

• poor leaving groups

  • generally, ethers do not undergo SN2 reactions

  • epoxides are an exception as they are more reactive than ethers

influence of solvents in SN2 reactions

• poor solvents comprise of an —OH or an —NH group

• good solvents do not have an —OH or an —NH group but are polar

• solvation - the process that occurs in the reactant nucleophile caused by protic solvents that slow the rate of SN2 reactions

  • a solvated anion is reduced in nucleophilicity due to enhanced ground-state stability

classification of solvents

• non-polar solvents hexane, benzene

• polar

  • polar protic

    • forms hydrogen bonds and are highly polar

    • H2O, MeOH

  • polar aprotic

    • medium range of polarity

    • increases the rate of SN2 reaction by increasing the ground energy of the nucleophile

    • high polarity gives it the ability to dissolve a number of salts, but they also dissolve metal cations instead of nucleophilic anions

    • the best solvent for SN2 reaction as they have strong dipoles but do not have —OH or —NH groups

    • tend to solvate metal cations rather than nucleophilic anions, resulting in “naked” anions of the nucleophile and makes the electronic pair of the nucleophile more available

    • HMPA, CH3CN, DMF, H2O, CH3OH

SN1 reactions

• nucleophilic substitution by an alternative mechanism

• substitution, nucleophilic, unimolecular

• tertiary alkyl halides react rapidly in protic solvents

general concept

• SN1 reactions are first-order reactions

• the rate equation does not contain the concentration of the nucleophile

• reaction rate formula

kinetics measurements

• rate-limiting step or rate-determining step

• the step that has the highest energy transition state than other steps in an organic reaction

energy diagram

• spontaneous dissociation of alkyl halide gives a carbocation intermediate

carbocations in SN1 reactions

• the carbocation causes a difference in the stereochemical result of an SN1 reaction as compared to an SN2 reaction

• characteristics

  • planar

  • sp2-hybridized

  • achiral

• a symmetrical intermediate carbocation reacts with a nucleophile equally from either sides to produce a racemic (a 50:50 enantiomer mixture)

• structure

  • carbocations are trigonal planar

  • the central carbon atom in a carbocation is electron deficient (it has only six electrons in its valence shell)

  • the p-orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction

  • general order of reactivity towards SN1 reaction: 3° > 2° > 1° > methyl

  • note that the more stable the carbocation formed, the faster the SN1 reaction

  • resonance stabilisation of allylic and benzylic cations

influence of the substrate

• stability of the carbocation intermediate determines the rate of the SN1 reaction

• stereochemistry

  • chiral substrate dissociates, yielding a planar, chiral carbocation intermediate that forms a racemic mixture with 50% experiencing inversion of configuration, and the other 50% experiencing retention of configuration

effect of leaving group on SN1 reactions

• the influence of the leaving group in SN1 is similar to that of SN2 reactions

• the leaving group is closely associated with the rate-smiling step

• leaving group reactivity: H2O > TosO- > I- > Br- > Cl- > HO-

• neutral water is the leaving group in SN1 reactions occurring under acidic conditions

the nucleophile in SN1 reactions

• the added nucleophile is not associated with the rate-limiting method of the SN1 reaction and hence has no influence on the reaction rate

effect of solvent in SN1 reactions

• according to the Hammond postulate, the factor (solvation of the carbocation) that increases the rate of an SN1 reaction also stabilizes the intermediate carbocation

• have a faster rate in strongly polar solvents than in less polar sovents

• solvation by protic solvents decreases the ground-state energy of the nucleophile which is not optimal for SN2 reactions

• solvation by protic solvents decreases the transition state energy leading to the carbocation intermediate which is favorable for SN1 reactions

allylic and benzylic halides

• primary allylic and benzyl substrates react well in both SN2 and SN1 reactions

elimination reactions

• a nucleophile/lewis base reacts with an alkyl halide resulting in a substitution or an elimination

• dehydrohalogenation

• Zaitsev’s rule for elimination reactions

  • in the elimination of H-X from an alkyl halide, the more highly substituted alkene product predominates

mechanisms of elimination reactions

• E1 reaction

  • breaking of C-X bond produces a carbocation intermediate that yields the alkene by base removal of a proton

• E2 reaction

  • simultaneous cleavage of C-H bond and C-X bond produces the alkene without intermediates

• E1cB reaction

  • unimolecular elimination of conjugate base

  • proton undergoes base abstraction, yielding a carbanion (R-) intermediate

  • carbanion loses X-, yielding the alkene

E2 reaction

• reaction involving the treatment of an alkyl halide with a strong base

• the most common elimination pathway

• abides by the rate law

deuterium isotope effect

• C—H bond is more easily broken than a corresponding C—D bond\

mechanism for a E2 reaction

• EtOH removes a β proton, C—H breaks, and a new π bond forms and Br begins to depart

• partial bonds in the transition state (C—H and C—Br) break, forming new π C—C bonds

• C=C is fully formed and the other products are EtOH and Br-

free energy diagram

geometry of elimination

• called periplanar geometry

• hydrogen atom, the two carbons, and the leaving group lie in the same plane

• syn periplanar - H and X are on the same side of the molecule

• anti periplanar - H and X are on the opposite sides of the molecule

cyclohexene formation

• cyclohexene rings need to posses anti-planar geometry in order to undergo E2 reactions

• hydrogen and leaving group in cyclohexenes need to be transdiaxial

E1 reaction

• unimolecular elimination

• comprises of two steps and involves a carbocation

• E1 reactions start out along the same lines as SN1 reactions

  • dissociation leads to loss of H+ from the neighboring carbon rather than substitution in SN1 reaction

• substrates optimal for SN1 reactions also work well for E1 reactions

E1cB reactions

• takes place through a carbanion intermediate

summary of reactivity based on degree of halide

methyl halide

• SN2

  • reaction is very fast

primary alkyl halides

• SN2

  • mostly the reaction that occurs

  • use of a good nucleophile is required

• E2

  • strong hindered base is required

  • hindered bases give mostly alkenes

• E1cB

  • carbonyl group comprising a leaving group two carbons away is required

secondary alkyl halides

• SN1

  • very little solvolysis is possible (for example, with H2O or MeOH)

• SN2

  • nucleophile in a protic solvent is necessary

  • mostly occurs when reacted with weak bases

• E1

  • occurs very little

• E2

  • a strong base is required

• E1cB

  • carbonyl group comprising a leaving group two carbons away is required

tertiary alkyl halides

• SN1

  • use of pure ethanol or water favors simultaneous reaction

  • very favorable with weak bases (for example, with H2O or MeOH)

• E1

  • use of pure ethanol or water favors simultaneous reaction

  • always competes with SN1

• E2

  • a strong base is necessary

• E1cB

  • carbonyl group comprising a leaving group two carbons away is required