A2 Substitution and Elimination

what does concerted mean

all bonds are made/broken at the same time

what is rate determined by for S_N2

activation energy

what are the important aspects for a leaving group X in a substitution reaction

• the C-X bond breaking

• the group X accepting the former bonding electrons to become a lone pair

what do good leaving groups have for SN2

weak C-X bonds and happy to accept electrons

low/negative pK_a values (eg counterions of strong acids)

halides as leaving groups

the hydrohalic acids are mostly strong and hence they are quite good leaving groups. fluoride is NOT a leaving group.

how are simple and complex halides made

simple - made by radical halogenation of alkanes

complex - made from alcohols

is hydroxide a good leaving group

no. alcohols cannot act as electrophiles in substitution reactions

the conjugate acid of hydroxide is water - not acidic, pK_a (H₂O) = 15. the leaving group property of the counterion (OH^-) from the strong acid is not met.

how can alcohols be made into good leaving groups

when does this work

protonate them to make the leaving group water, whose conjugate acid is H₃O⁺ - a strong acid. pK_a = -3.

only works with a narrow range of non-basic nucleophiles eg Cl, Br, I. most nucleophiles are also good bases and will just react with the acid in a neutralisation reaction.

chlorination of alcohols

bromination of alcohols

what can be done to alcohols apart from making halides to turn them into good leaving groups

turn the into sulfonate esters

sulfonic acids are very strong (approx pK_a 3) so sulfonate ions are excellent leaving groups

3 examples of sulfonate esters

• para-toluenesulfonate (tosylate)

• methanesulfonate (mesylate, MeSO₃^-, MsO^-)

• trifluoromethanesulfonate (triflate, CF₃SO₃^-)

tosylate

para-toluenesulfonate

single bonded O not in Ts group

mesylate

methanesulfonate (MeSO₃^-, MsO^-)

the single bonded O is indeed not part of the group :(

triflate group

trifluoromethanesulfonate (CF₃SO₃^-)

single bonded O not in Tf group

production of tosylate from phenol

alkoxides as leaving groups

not good leaving groups - conjugate acids are alcohols (pK_a 16-18) so cannot be used as SN2 electrophiles

exception to alkoxides as leaving groups

cyclic three-membered ethers (oxiranes/epoxides) are very good electrophiles despite the alkoxide being a poor leaving group

this is because the C-O bond is unusually weak because of the severe angle strain within the three-membered ring. the relief of this angle strain on opening of the epoxide provides the extra driving force to overcome the otherwise unfavourable formation of the alkoxide

mechanism/products/reagents/conditions/explanation

effect of substitution on the electrophile on SN2 reactivity

reactivity decreases with increasing substitution around the carbon undergoing attack (ie rate of reaction decreases across the series methyl > primary > secondary > tertiary alkyl group)

effect of neighbouring π systems in electrophile on SN2

orbitals? stages?

3 examples

rate is increased by presence of neighbouring π systems

the π system overlaps with the p-orbital on the carbon in the transition state, stabilising it and lowering the energy barrier. π systems are also EWG helping make the carbon more electrophilic and susceptible to nucleophilic attack.

this makes allylic, benzylic and α-carbonyl electrophiles good SN2 substrates

inversion of stereochemistry for SN2 reactions

stereochemistry in SN1 reactions

with EtOH

a racemic (1:1) mixture of the two enantiomers is formed, as the stereochemistry of the starting material is lost in the planar carbocation intermediate, and this intermediate can be attacked from either face with equal likelihood, giving the 1:1 mixture

what makes a good nucleophile

high-lying HOMO (often meaning a readily donatable lone pair) allowing effective overlap with the LUMO of the electrophile (often C-X σ^*)

better nucleophile of same element

for a given element, the more basic a species is, the better a nucleophile it is

nucleophiles showing basicity condition for SN2 + examples that are not SN2 nucleophiles

water and perchlorate are basic but not nucleophiles

note about water and OH^- pK_as - the pK_a for OH^- is water’s pK_a, while the pK_a for water is H₃O⁺’s, as these are their conjugate acids

limitations to basicity correlation

• does not apply to nucleophiles formed from different elements (cannot compare N and O for example)

• steric effects - the bigger a nucleophile is, the poorer it is

hydroxide as an SN2 nucleophile

• hyroxide is a good SN2 nucleophile and can be used for example to form alcohols from alkyl halides

• however, it is also a good base (pK_a H₂O = 15) so there is a competing reaction (E2). the balance between SN2 and E2 will depend on how good of an Sn2 electrophile the other reactant is (if it is not good SN2 will be slow and E2 will dominate)

carboxylates as SN2 nucleophiles

• good SN2 nucleophiles (less reactive than hydroxide but still highly competent)

• because they are not basic (counterions of a weak acid) they do not cause complications with E2, and there is only SN2

• this is used to perform 2 step conversion of alkyl halides to alcohols where the use of hydroxide is unsuitable due to E2. clean SN2 with carboxylate is followed by ester hydrolysis under basic conditions

2 methods to convert alkyl halide into alcohol

• 1 step with OH easier/faster except for competition with E2

• where E2 is a problem, 2 step conversion with carboxylate is used

phenoxides as SN2 nucleophiles

• anions of phenols (phenoxides) are good SN2 nucleophiles

• they are only weakly basic (pK_a of weak acids = ca. 10) so they do not cause complications with E2

how are phenoxides made

• can prepare separately or

• can make them in a single step by treating then phenol with a base like hydroxide (as PK_a is approx 15 it can quickly and fully deprotonate then phenol) in the presence of the electrophile

this reaction is known as Williamson ether synthesis. it is widely used, eg with the above reaction synthesising the antidepressent fluoxetine (Prozac)

alkoxides as SN2 nucleophiles

• anions of alcohols (alkoxides) are very good SN2 nucleophiles

• as they are more basic than OH (OH pK_a 15, alcohols 16-18) they can also cause problems with E2

SN2 and E2 competition

generally, if both nucleophile and electrophile (especially) are relatively non-hindered, SN2 will dominate. increasing hindrance on either increases E2

preparation of alkoxides

• alcohols are not very acidic so the anions need to be pre-formed using a relatively strong base (OH not strong enough), sodium hydride is common

thiols as SN2 nucleophiles

• can use to make sulfides (also known as thioethers) by SN2.

• more acidic than alcohols (pK_a PhSH = 6.5 vs PhOH = 10) so hydroxide fine as a base

thiolates as SN2 nucleophiles

• better nucleophiles than their oxygen equivalents (thiols) despite being less basic

• PhS^- is ca. 25,000 times more nucleophilic than PhO^-)

what happens to nucleophilicity as you go down a group

nucleophilicity increases as higher energy HOMO is better matched to LUMO

mechanism + explanantion

• SN2

• nitrogen is a more basic atom (better lone pair donor) than oxygen and neutral amines are excellent SN2 nucleophiles

• but it can be difficult to stop the reaction after one substitution and often different methods are used to make substituted amines

electrophile for SN2 with amine nucleophiles

epoxides

reactions are more easily controlled in terms of over-alkylation (nucleophilicity of amino alcohol product is attenuated by hydrogen bonding)

drug synthesis using amines as SN2 nucleophiles

1,2-aminoalcohols are found in many pharmaceuticals such as beta-blockers, asthma treatments and protease inhibitors

azide as SN2 nucleophiles

• excellent SN2 nucleophile (small, linear molecule with negative charge on the nitrogen)

• the azide function can also be reduced to give a primary amine, which is a much more reliable way of making amines through SN2 than by using ammonia as there is no possible overalkylation of the azide

cyanide as an SN2 nucleophile

• cyanide anion is a very good SN2 nucleophile (small, negatively charged on carbon)

• products contain one more carbon than the starting materials - they have been homologated

what is homologation

a process that turns the product into the next member of the homologous series - ie adds one carbon to the chain

what can cyanide groups be converted into

other useful groups eg carboxylic acids (by hydrolysis) or primary alkylamines (by reduction)

acetylide as an SN2 nucleophile

ethyne (acetylene) is relatively easy to turn into an anion known as acetylide. you can buy lithium acetylide, which is a good SN2 nucleophile

how are acetylide anions made

use a very strong base such as sodium amide

the resulting alkynes can be used to selectively make either E or Z alkenes (don’t need details for now)

when can elimination occur instead of substitution

if a carbocation is generated but there is no nucleophile to react with it, a proton can be lost instead in an elimination reaction

E1 of C(Me)₃X

rate profile and rate equation for E1 of C(Me)₃X

rate = k[XC₄H₉]

kinetics of E1 and RDS

RDS is formation of high-energy cation so E1 follows unimolecular kinetics as SN1 does

E1 of tertiary alcohols

regiocontrol in E1

• more than one alkene can be formed from intermediate carbocation

• E1 tends to give the more substituted alkene as the major product

kinetics leading to regiocontrol in E1

• more substituted is usually more stable product but also

• pathway to the major product from the common intermediate is lower in energy than the pathway to the minor product so it proceeds faster

stereocontrol in E1

• for some substrates, geometric isomers can be formed from the intermediate.

• E1 gives the E-alkene as the major product

kinetics leading to stereocontrol in E1

• the E-alkene is more stable than the Z but also

• pathway to E from common intermediate is lower in energy and hence faster than Z

E2 of isopropyl chloride

kinetics of E2 (type, rate profile, description, RDS)

• base and electrophile both RDS (one step)

• bimolecular, concerted, single-step, all bonds broken and formed at same time

• rate = k[ClC₃H₇] [OH^-]

good electrophiles for E2

• unlike the other 3 mechanisms, E2 is not too fussy about electrophile structure

• as long as there is an abstractable proton on the next carbon which can adopt suitable reactive shape (see stereo)

good leaving groups for E2

• same as SN2

• so halides, sulfonate esters like tosylates, epoxides

• NOT protonated alcohols - incompatible with the base

bases for E2

• as seen in SN2, many nucleophiles are also basic and cause mixtures of SN2 and E2

• can get clean E2 with either tertiary alkyl halides (no SN2) or very bulky bases which don’t act as nucleophiles

stereoelectronics of E2

• as with SN2, because all bonds are formed and broken at once, the arrangement of the reacting orbitals in space must be considered to ensure the electrons can reorganise smoothly into the new bonding orbitals

• most favourable arrangement of E2 has C-H breaking at 180° to the C-X breaking, which maximises overlap of the breaking C-H bond with C-X σ^*, and pushing electrons into this breaks the C-X bond

• this arrangement is called anti-periplanar and only this formation can react to form a product (see example E2 from another flashcard - the orange product does not form)

regiochemistry in E2

where there is more than one possible site for a proton to be abstracted in E2, we find the major product is the less substituted alkenes

kinetics leading to regiochemistry in E2

• the less substituted alkene is actually the less stable alkene

• it arises because the transition state for attack on the more accessible proton is lower in energy than the more crowded transition state for attack at the less accessible proton

• it is useful that this is the complementary regiochemical outcome to E1

stereochemistry in E2

where two possible alkene stereoisomers are possible, the E alkene is the major product

kinetics leading to stereochemistry of E2

• E alkene is most stable but again is not why it forms

• it is the faster formed product because the transition state leading to it is less crowded than for Z

• this means both E1 and E2 favour E and so Z must be made by other means

methyl group summary for sub&elim

SN2 with good nucleophiles, else no reaction

primary alkyl group summary for sub&elim

• SN2 with good nucleophiles

• SN1 if R is alkene or aromatic

• E2 with strong base

secondary alkyl group summary for sub&elim

• SN2 with good nucleophiles

• SN1 with weaker nucleophiles

• E2 with strong base

• E1 with poor bases or in acid

tertiary alkyl group summary for sub&elim

• SN1 with any nucleophiles

• E2 with strong base

• E1 with poor bases or in acid

• NO SN2