Leaving Group of Substrate Important

Home , Leaving group

1 Recap... • Last two lectures we looked at substitution reactions • We found that there we two (extreme) mechanisms • SN1

H H H H H PhS R H R Br R SPh Br

• And SN2

H H H H PhS + Br R Br PhS R

• We looked at many of the factors that inﬂuenced which ..mechanism was operating... • Now we will turn our attention to elimination reactions 2 Elimination reactions

NaOH NaOH or low Br H2O OH concentration

• You have seen SN1 substitution • Reaction not sped up by altering nucleophile - it is not in RDS • In fact if we increase the amount / concentration of nucleophile we get the following...

high O H + + + Br Br OH concentration H H

• We observe an elimination reaction • Overall HBr is lost from the molecule • Isn't chemistry fun - these are the same conditions as substitution! • Next two lectures will look at the mechanisms for elimination • And how we control the nature of the reaction we observe... 3 Elimination, bimolecular E2

O H Br HO Br H H

• E2 - Elimination bimolecular or 2nd order reaction • 2 molecules in the RDS or transition state

H H H H H C H C H H C Br Br H O H C H O H C C H H H H C H C H H H • Two molecules in the rate determining step • So both the base and the substrate control the reaction • Both carbon skeleton & leaving group of substrate important

In substitutions nucleophile acts as a nucleophile & attacks carbon In eliminations nucleophile acts as a base & attacks proton 4 Elimination, bimolecular E2: MO • Little confusing as need bonding & anti-bonding in same diagram! • Orbitals need to be parallel for maximum overlap • Favoured conformation is anti-periplanar (staggered)

HO HO HO HO

H CH CH3 H H 3 H H H H CH H C CH3 C 3 H C Br H C H H H H Br Br H Br H orbitals orbitals parallel parallel bonding orbitals anti-bonding orbitals

HO π H orbital CH3 σ CH orbital 3 H CH3 H CH3 H CH ≡ H CH H 3 3 H Br σ∗ orbital As deprotonation occurs σ C-H overlaps with σ* C-Br resulting in C-Br bond breaking and a new π bond forming 5 Elimination, unimolecular E1

O O H2SO4 O H H S OH HO OH

O O H2SO4 H + S HO O

H RDS O H OH H

• E1 - Elimination unimolecular or 1st order reaction • 1 molecule in the RDS

O H H H HO S O H H H C H H C H H C H H H H H C H O H H O H O H H C C H C C H C C C C H RDS H H H C H H H C H H H C H C H H H H H 6 Elimination, unimolecular E1: MO

HO3S O HO3S O

H CH3 H CH3 H CH3 H CH3 H O H H CH3 H H CH3 H H orbitals parallel

• One molecule in rate determining step • So only the substrate is important (RDS = carbocation formation) • Both the carbon skeleton & leaving group of substrate important

So what factors favour elimination vs substitution & E1 vs E2? 7 Nucleophilicity vs basicity • We have seen a nucleophile attack TWO electrophilic sites in the same molecule (H or C) • What is the difference? • Nucleophile forms new bond by donating 2 electrons to an atom (not H) • Base forms new bond by donating 2 electrons to H The more basic the nucleophile the more elimination!

EtOH Cl OEt Cl EtO Na weak base strong base

O Cl H Et Et H Cl EtO O H

Stronger the base - more likely to attack H 8 Nucleophilicity vs basicity: Size • In substitution reactions nucleophile must approach carbon • Hard to get passed susbtituents • Attacking exposed H much easier - encouraging elimination • Bigger the nucleophile more chance of elimination • t-BuOK very bulky - invariably gives elimination

Br NaOH OH small nucleophile

H H HO

Br KOt-Bu bulkly base

O H H H

Br 9 E2 elimination • Nearly all substrates can undergo E2 elimination • If strong (hindered) base present then reaction is E2 primary halide

H t-BuOK OEt Br OEt O OEt E2 OEt secondary halide HO HO DBN N N H O O O E2 O DBN I tertiary halide

X H H3C CH 2 E2 HO H3C HO Br X H3C Br H3C H3C 10 E1 & E2 eliminations

stabilised carbocation X R R tertiary R H

H X H R R allylic R H substrates readily H eliminate by E1 X H R R benzylic R Ar Ar Ar H

X H H α-hetero H substituted H RO RO RO less stable carbocation secondary X substrates may H R eliminate by E1 R R unstable carbocation X substrate never primary eliminates by E1 R R X • Only substrates that can stabilise a cation can eliminate by E1 • All of the above may eliminate by E2 11 The leaving group: amines

• So far seen alkyl halides & protonated alcohols as leaving groups • Other groups can as well • Better the leaving group - faster elimination • No change to mechanism as leaving group in RDS of both E1 & E2 • Below, both E1 or E2 possible - but which occurs?

H2O KOH NMe3 NMe3 heat heat I OH

NMe3 H NMe3

• Primary position so can't form cation • Tertiary position so could form cation • Can't be E1 • Could be E1 or E2 • Strong base allows E2 • Weak base so must be E1 12 The leaving group: alcohols

• Hydroxyl group good leaving group if protonated • Substrate must be able to undergo E1 Ph OH Ph H2SO4, H2O

E1 O O • HO is never a leaving group in E2 H • Reaction uses base & this would H ..deprotonate hydroxyl group Ph Ph O H H O R H Base R O H Base

O O O H H • Must convert alcohol to good leaving group • Could use tosylate (last lect.) or below is mesylate (very similar) O O O Me OH Me OMs Me N N MsCl N DBU N O MsCl = Me S Cl DBU = N Et3N O O N O N Pr E2 O N Pr Me Me Me