Chapter 7- alkyl halides: nucleophilic substitution and elimination reactions (copy)

substitution

reaction in which an alkyl halide (substrate) is treated with a nucleophile

nucleophile replaces halogen

elimination reaction

reaction in which an alkyl halide (substrate) is treated with a base

alkene (pi bond) is formed

new molecule does not have base or halogen attached

leaving group

the group separated from a compound

e.g. halogens in alkyl halides

good LGs: weak (stabilized) bases, conjugate bases of acids with pKa < 0

examples of good leaving groups

Weak bases / pka < 0

I^-

Br^-

Cl^-

RSO₃^- (sulfate ions)

H2O

(note: leaving groups above are listed in order of decreasing stability, so I^- is best and H2O is not as good)

OTs (excellent)

examples of bad leaving groups

pka > 0

F^- (closest to good)

H^-

CH3CH2O^-

H2N^- (worst)

S_N2 reaction

reaction in which an alkyl halide is treated with a strong nucleophile

substitution reaction, involving a nucleophile (Nu), bimolecular

concerted mechanism (nucleophile attacks and LG leaves at the same time)

usually exhibits Walden inversion

rate = k[alkyl halide][nucleophile] (second order)

rate of an S_N2 reaction

rate = k[alkyl halide][nucleophile]

sensitive to number of substituents at the alpha position (degree of the alpha carbon)

methyls and primary alkyl halides are best, secondary is okay, tertiary is negligible (cannot be performed because of too much steric hindrance)

also sensitive to substituents attached to beta carbon, but not as much (same concept applies to beta carbons as to alpha carbons)

Walden inversion

in an S_N2 reaction, wedges become dashes and vice versa

usually R becomes S and S becomes R (but not always)

happens because of back-side attack

back-side attack

requirement for a Walden inversion in S_N2 reaction

lone pairs of Lg create areas of high electron density that block the front side of the substrate

MO theory: electron density flows from HOMO of nucleophile to LUMO of electrophile

Nu can only attack from the back side

stereospecificity

the dependence of a product’s configuration on the starting material’s configuration

nucleophilicity

the rate at which a Nu will attack an electrophile

strong Nus give faster S_N2 reactions, weak Nus give slower reactions

strong Nu is required for S_N2 to be efficient

influenced by charge and polarizability

charge: negative charge makes a stronger Nu than a neutral charge (e.g. OH^- vs H₂O)

polarizability: ability of an atom to distribute its electron density unevenly as a result of external forces (directly related to size and number of electrons that are distant from nucleus) (e.g. halogens are strong Nus, alcohols are weak)

E2 reaction

a reaction in which an alkyl halide reacts with a strong base

elimination reaction, bimolecular

concerted mechanism

beta elimination

aka 1,2-elimination or dehydrohalogenation

a proton is removed from beta position, halide is ejected as an LG (X^-) from alpha position, double bond forms between alpha and beta positions

rate of an E2 reaction

rate = k[alkyl halide][base]

any degree of alkyl halide works, because protons can be abstracted even from a bulky tertiary substrate

relative stability of isomeric alkenes

tetra substituted is most stable, then trisubstituted, then disubstituted, monosubstituted is least stable

because of hyperconjugation

hyperconjugation

stabilizing effect that allows alkyl groups to stabilize a carbocation by donating electron density to the neighboring sp²-hybridized C

enables delocalization of electron density

regioselectivity

a reaction that can produce two or more constitutional isomers, but produces one as the major product

occurs when beta positions of a molecule are not identical, so the double bond can form in two different regions of the molecule

regioselectivity of E2 reactions

depending on where the double bond forms and the steric bulk of the molecules, different products can be formed

Zaitsev product and Hofmann product

Zaitsev product

more substituted alkene

usually the major product, but not always (e.g. when both substrate and base are sterically hindered)

Hofmann product

less substituted alkene

e.g. formed when substrate and base are both too bulky to form the Zaitsev product

stereoselectivity of E2 reactions

trans product is major

cis product is minor

Hammond postulate: transition state for formation of trans alkene is more stable than transition state of cis alkene

stereospecificity of E2 reactions

molecule must be anti-periplanar

anti-: proton and LG must be anti on a Newman projection

periplanar: dihedral angle must be 180* (or close to 180*)

stereoselective vs stereospecific E2 reaction

stereoselective: substrate is not necessarily stereoisomeric, but substrate can produce two stereoisomeric products with one in higher yield

stereospecific: substrate is stereoisomeric, stereochemical outcome is dependent on which substrate is used

S_N1 reaction

reaction in which an alkyl halide is treated with a weak nucleophile

substitution, involves a nucleophile, unimolecular

stepwise mechanism

solvolysis: solvent molecule functions as the attacking nucleophile

step 1: LG leaves, creates carbocation intermediate

step 2: Nu attack

if Nu is uncharged, step 3: proton transfer

generally not observed at sp² hybridized centers (because loss of LG would result in an unstable carbocation)

E1 mechanism

tertiary alkyl halide undergoes ionization in polar solvent, solvent acts as base and deprotonates intermediate carbocation

elimination, unimolecular

stepwise mechanism

step 1: LG leaves

step 2: proton transfer, electrons move to create double bond

generally not observed at sp² hybridized centers (because loss of LG would result in an unstable carbocation)

rearrangements for S_N1 and E1

hydride shift and methyl shift

occur to create a more stable tertiary carbocation

(note: a methyl shift may be drawn at the same time as everything else in an S_N1 process, but it is still S_N1 and not concerted)

stereochemistry of S_N1 reactions

retention of configuration: intermediate carbocation can be attacked from either side; does not require backside attack, so no Walden inversion

however, Nu will attack more often on the side opposite the LG, so there is slight preference to inversion over retention

predicting products: substitution vs elimination

step 1: determine function of reagent (substitution when reagent functions as Nu, elimination when reagent functions as base)

step 2: determine expected mechanism(s) based on substrate degree and reagent identity

step 3: consider regiochemical and stereochemical outcomes

reagent and substrate combinations for S_N2

1* substrate and strong B/strong Nu (most)

1* substrate and weak B/strong Nu

2* substrate and strong B/strong Nu (some)

2* substrate and weak B/strong Nu

reagent and substrate combinations for E2

1* substrate and strong B/weak Nu

1* substrate and strong B/strong B (some)

2* substrate and strong B/weak Nu

2* substrate and strong B/strong Nu (most)

3* substrate and strong B/weak Nu

3* substrate and strong B/strong Nu

reagent and substrate combinations for S_N1

3* substrate and weak B/strong Nu

3* substrate and weak B/weak Nu (about half)

reagent and substrate combinations for E1

3* substrate and weak B/weak Nu (about half)

regiochemical and stereochemical outcomes for S_N2

regiochemical: Nu attacks alpha position, where LG is connected

stereochemical: Nu replaces LG with inversion of configuration

regiochemical and stereochemical outcomes for E2

regiochemical: Zaitsev product is generally favored over Hofmann, unless sterically hindered base is used

stereochemical: stereoselective; trans will be favored over cis when possible. Stereospecific; when beta position of substrate has 1 proton, anti-periplanar alkene will be obtained

regiochemical and stereochemical outcomes for S_N1

regiochemical: Nu attacks carbocation which is generally where LG was connected (unless hydride shift or methyl shift occurred)

stereochemical: Nu replaces LG to give nearly racemic mixture, with slight preference for inversion over retained configuration

regiochemical and stereochemical outcomes for E1

regiochemical: Zaitsev product always favored over Hofmann

stereochemical: stereoselective; when applicable, trans alkene will be favored over cis

other substrates for substitution and elimination reactions

tosylates: type of sulfonate ion, one of the weakest known bases

alcohols: do not undergo S_N2 reactions when treated with strong Nu, but can undergo substitution reactions under strong acidic conditions (become good LG when protonated)

solvent effects in S_N2 reactions

Nu and LG are generally ionic, polar solvent needed to solvate them

polar solvents also help stabilize transition state

2 types of polar solvents: protic (H connected directly to electronegative atom) and aprotic (Hs are not connected to electronegative atom)

reactions occur much faster in polar aprotic solvents compared to protic (e.g. DMF)

reason: protic solvents have electronegative atoms with lone pairs and can form H-bonds with halogen, stabilizing them

aprotic solvents can only stabilize cations, not anions

solvent effects in S_N1 reactions

polar protic solvents are more suitable

reason: protic solvents stabilize ionic intermediates and transition states (give smaller E_a)