Lecture 3

Chapter 7 (only 7.3.1): Hammond postulate TOOLS

Chapter 8 (8.1, 8.2, 8.3, 8.4.1, 8.8)
Isotope effects, Substituent effects, Other exps for studying mechanisms

Chapter 9 (only 9.3) Brønsted acid-base catalysis

Appendix 5 electron pushing

Chapter 10 addition and/or elimination reactions REACTIONS

Chapter 11 substitution reactions
thermal rearrangements + isomerisations

Chapter 15 thermal pericyclic reactions

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Some rules on drawing up plausible mechanisms

1 - Find correspondence between atoms in reactant and product

any rearrangements needed?

2 – Look for a path to the product

identify bonds to be made or broken
3 – Identify possible electron sources and sinks

4 – Proceed through intermediates of the lowest possible energy

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Electron pushing – a case study
Acid catalysed enamine hydrolysis

3
Radical reactions

- Source: any bond, lone pair or single electron (no analogy with nucleophiles)

- Sink: any site that can accept a single electron (no analogy with electrophiles)

Common radical reactions:

- homolytic cleavage

- radical recombination

- hydrogen abstraction

- radical addition to double bond

- electron transfer to sigma or pi bond

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Example: HBr addition to alkenes

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Chapter 10: Mechanisms of reactions involving additions
or/and eliminations

Central questions: How to come up with a plausible mechanism

Definitions:
reaction = redistribution of the connectivity of atoms within a chemical structure
or between chemical structures
mechanism = set of individual steps involved in a reaction

Vantage points:
1 - Electrostatics
2 - Lewis acid Lewis base interactions
3 - Electrophile - nucleophile interactions
4 - Orbital overlap

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1- Electrostatics

Electrostatics are a good starting point for predicting reactivity

Simplistic view: combine the positive region of one molecule with the negative
region of another

However: in a reaction the electrons are not static

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Pauling electronegativities of atoms

H 2.1
B 2.0
C 2.5
N 3.0
O 3.5
F 4.0
Cl 3.0
Br 2.8
I 2.5
Li 1.0
Na 0.9
K 0.8
Mg 1.2
Ca 1.0
Al 1.5
Si 1.8
P 2.1
S 2.5
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2- Nucleophile-electrophile interactions

Nucleophile = compound seeking a nucleus (i.e. positive charge)

carries a (partial) negative charge

Electrophile = compound seeking electrons (i.e. negative charge)

carries a (partial) positive charge

Nucleofuge = nucleophile departing from a molecule instead of adding to it

Electrofuge = electophile departing from a molecule instead of adding to it

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3- Lewis acid – Lewis base interactions

Lewis acid = electron pair acceptor

Lewis base = electron pair donor
where electron pair = lone pair, or  or  bond

Hard Lewis acids prefer hard Lewis bases

Soft Lewis acids prefer soft Lewis bases
Gilbert N. Lewis 1875-1946

Purified D2O
Note:
Coined the term ‘photon’
Lewis acid/base = thermodynamic descriptor
Developed Lewis-acid-base theory
Nucleophile = kinetic descriptor Photochemistry
Reformulated chemical thermodynamics

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4 – Orbital interactions

Reactions involve mixing filled orbitals with unfilled orbitals

electrophile / Lewis acid

acceptor orbital

nucleophile / Lewis base

donor orbital

Reaction are easiest when donor and acceptor orbitals have similar energies
Compare HOMO of nucleophile / Lewis base / donor
LUMO of electrophile / Lewis acid / acceptor

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How do radical reactions fit in?

Radicals can have nucleophilic or electrophilic character or both

Chain mechanisms

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The big picture of organic reactions
What are the elemental types of reactions?

Classification by kind of reaction

Additions to  bonds (Ad)
Eliminations to form  bonds (E)
Substitutions on  bonds (S)
Others
Refinement with nature of reactant
Electrophilic (E)
Nucleophilic (N)
Radical (R, or H for homolytic)

Refinement with molecularity of reaction

Unimolecular (1)
Bimolecular (2)

See appendix 6 for more details

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 ADDITION REACTIONS
Feature unsaturated compounds: alkenes, alkynes, carbonyls and arenes

Electrophilic additions Nucleophilic additions

Carbonyls: hydration Carbonyls: cyanohydrin
Alkenes and alkynes: hydration Grignard
HX addition LAH reduction
halogen addition Alkenes: conjugate addition
hydroboration
epoxidation

Radical additions Carbene additions (and insertions)

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Hydration of carbonyl compounds

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General vs specific acid catalysis - refreshing your memory
‡
General Go  Go

O H A
acid Nuc
O
Nuc
catalysis Nuc

Nuc HA
O OH
O
OH
Nuc
or Nuc
HA HA
A
protonation in rds A

so [HA] in rate law

reaction coordinate reaction coordinate

Go Nuc
Specific
O
acid catalysis Nuc
H

A OH
O
Nuc
pre-equilibrium HA
A
only 'pH' matters
so [HS+] (i.e. [H3O+])
in rate law
see D&A 9.3 reaction coordinate 16
 Acid-catalyzed hydration of carbonyl compounds
Mechanism depends on conditions:
Moderate pH
H2O only weakly nucleophilic and carbonyl only weakly basic so:
concerted proton transfer

‡
Go

O H A
OH2

Nuc

O
OH
HA Nuc

reaction coordinate

Very low pH: protonation pre-equilibrium so specific acid catalysed

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Hydration of carbonyl compounds (cntd)
Basic conditions: general base catalysed

The same reaction can proceed through different mechanisms

depending on the experimental conditions

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 Brønsted  values - refreshing your memory
determined from slope of plot of log(kobs) vs. pKa of acid catalyst
 value = exent of proton transfer in the TS

see D&A 9.3 19

 General acid catalysed ketone hydration

Experiments: linear Brønsted plot = constant  value as you change the

pKa of the acid

Conclusion: extent of proton transfer unchanged as the acid pKa changes!!

But:
Hammond postulate: stronger acid  IS energy increases  TS more like IS

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 Analysis in terms of More O' Ferral Jencks diagram

Conclusion: stronger acid means TS already reached at reduced extent of

bond formation with nucleophile

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Carbonyl hydration is generally reversible

[geminal diol]
K=
[carbonyl]

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Connection to hemiacetals

Nucleophile is an alcohol rather than water

Do you know an example of a class of stable hemiacetals?

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