General Chemistry: Recap of the previous lecture

lecture 3
Describing a reaction (equilibrium constant, Gibbs free
energy, enthalpy, entropy, bond dissociation energies)

Energy diagrams and transition states

Carbocation stability

The Hammond postulate

Carbocation rearrangements

Kinetic versus thermodynamic control of reactions

Definition of catalysis (homogeneous, heterogeneous,

enzyme)
[ From : Nature Chemistry 2021, 13, 977–981 ] 1 2

Substitution reaction
Plan for today
Reaction when one group is replaced by another
Nucleophilic substitution
Nucleophilic substitution – a nucleophile replaces another group on a
Nucleophilic addition carbon atom

Electrophilic substitution – an electrophile attacks an aromatic molecule

Nucleophilic acyl substitution and replaces a hydrogen atom

Electrophilic substitution

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Nucleophilic substitution: discovery by Paul Walden in 1896 Nucleophilic substitution: mechanism

Polarimetry as a key
analytical tool

1937 : E. D. Hughes and Christopher Ingold formulated SN2 reaction -

short for substitution, nucleophilic, bimolecular

Change, or inversion, in configuration at the chirality center

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The mechanism of the SN2 reaction The transition state of an SN2 reaction

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 Steric hindrance in SN2 reaction This lack of reactivity is due to steric factors: the incoming
nucleophile would have to approach in the plane of the
carbon-carbon double bond and burrow through part of the
molecule to carry out a backside displacement

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Nature of nucleophile in SN2 reaction Nature of nucleophile in SN2 reaction

Nucleophilicity roughly parallels basicity

Nucleophilicity usually increases going down a column of the periodic table

Negatively charged nucleophiles are usually more reactive than neutral ones
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 The Role of Leaving Group To carry out an SN2 reaction with an alcohol, it’s necessary
to convert the −OH into a better leaving group

The best leaving groups are those that best stabilize the negative charge
in the transition state. The greater the extent of charge stabilization by
the leaving group, the lower the energy of the transition state and the
more rapid the reaction.

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Epoxides due to the angle strain in the three-membered
ring are much more reactive than other ethers
The role of solvent
The rates of SN2 reactions are strongly affected by the solvent
Protic solvents - those that contain an -OH or -NH group - are generally the
worst for SN2 reactions
Polar aprotic solvents which are polar but don’t have an -OH or -NH group
are the best

Attack on less hindered carbon

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 Acetonitrile (CH3CN), dimethylformamide [(CH3)2NCHO, abbreviated DMF], We might expect the reaction of a tertiary substrate (hindered) with
dimethyl sulfoxide [(CH3)2SO, abbreviated DMSO], and water (neutral, protic) to be among the slowest of substitution reactions
hexamethylphosphoramide {[(CH3)2N]3PO, abbreviated HMPA} can dissolve Remarkably, however, the opposite is true !
many salts because of their high polarity, but they tend to solvate metal
cations rather than nucleophilic anions. As a result, the bare unsolvated anions
have a greater nucleophilicity and SN2 reactions take place at correspondingly
faster rates.

Alternative substitution mechanism !

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SN1 reaction for substitution, nucleophilic, unimolecular SN1 reaction takes place by loss of the leaving group before the nucleophile
approaches resulting in carbocation (slow rate-limiting step), and the
intermediate carbocation is then immediately trapped by the nucleophile
water in a faster second step

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 Stereochemistry of the SN1 reaction Ion-pairs in an SN1 reaction. The leaving group shields one side of the
carbocation intermediate from reaction with the nucleophile, thereby leading
to some inversion of configuration rather than complete racemization

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The Hammond postulate - reminder Corollary to Hammond postulate: The more stable the carbocation
intermediate, the faster the SN1 reaction!
Transition states (TS) are high-energy activated complexes that occur transiently.
We cannot observe transition states directly!
Hammond postulate says that we can get an idea of a particular transition state’s
structure by looking at the structure of the nearest stable species.

(a) Transition state for an endergonic reaction structurally resembles the product
(b) Transition state for an exergonic reaction structurally resembles the reactant

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Allylic and benzylic C-X bonds are about 50 kJ/mol (12 kcal/mol) weaker
than the corresponding saturated bonds and are therefore more easily
broken
Primary allylic and benzylic substrates are particularly reactive in SN2
reactions as well as in SN1 reactions.
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The leaving group in SN1 reactions
The leaving group is directly involved in the rate-limiting step
The best leaving groups are those that are most stable; that is, those that
are the conjugate bases of strong acids
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The nucleophile in SN1 reaction
Because the SN1 reaction occurs through a rate-limiting step in which the
added nucleophile has no part, the nucleophile can’t affect the reaction
rate. The reaction of 2-methyl-2-propanol with HX occurs at the same rate
regardless of whether X is Cl, Br, or I. Furthermore, neutral nucleophiles are
just as effective as negatively charged ones, so SN1 reactions frequently
occur under neutral or acidic conditions
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 Solvent effects in the SN2 reaction are due largely to stabilization or Biological examples: synthesis of geraniol
destabilization of the nucleophile reactant, while solvent effects in the
SN1 reaction are due largely to stabilization or destabilization of the
transition state

The Hammond postulate says that any factor

stabilizing the intermediate carbocation should
increase the rate of an SN1 reaction

Solvation with polar solvent

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The biosynthesis of epinephrine from norepinephrine To summarize …

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Nucleophilic addition Some typical nucleophilic reactions of aldehydes
and ketones

Nucleophilic oxygen reacts

with acids and electrophiles

Electophilic carbon reacts

with bases and nucleophiles

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Alcohol formation

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Mechanism of acid-catalyzed imine (Schiff base) formation Mechanism of acid-catalyzed hemiacetal and acetal formation

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The formation of hemiacetals and acetals is a central part

of carbohydrate chemistry

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Conjugate (1,4) Nucleophilic Additions

Conjugate addition occurs because the electronegative oxygen atom of

a,b-unsaturated carbonyl compound withdraws electrons for the b-carbon
making it more electron-poor and electrophilic

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Nucleophilic acyl substitution

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 Mechanism of nucleophilic acyl substitution

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Mechanism of carboxypeptidase-catalyzed hydrolysis of

the C-terminal amide bond

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