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04-BS-12 · May 2017

Question 3 of 13: Penicillin G — Why the β-Lactam Amide Is the Reactive One

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Notes on this paper

National Exam 04-BS-12, Organic Chemistry — May 2017. 3 hours, closed-book examination (no textbook aid beyond one double-sided aid sheet); a Casio or Sharp approved calculator is permitted. The paper prints thirteen questions using plain "Question N:" numbering; all thirteen are answered in full below.

Reference texts: McMurry, Organic Chemistry, 9th ed. (functional-group reactivity, amide/β-lactam resonance, stereochemistry and specific rotation, SN1/SN2 and epoxide-opening regiochemistry, cyclohexane conformational analysis, IR/NMR spectroscopy, electrophilic aromatic substitution and multi-step synthesis design, polymer/step-growth chemistry); Atkins, Physical Chemistry, 11th ed. (entropy of intramolecular vs. intermolecular reactions).

Question 3: Penicillin G — Why the β-Lactam Amide Is the Reactive One

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

penicillin G — the strained, exocyclic-substituent-bearing β-lactam ring vs. the acyclic phenylacetamide side-chain amide

The four-membered β-lactam ring amide is far more reactive (more easily hydrolysed/acylated) than the ordinary, acyclic amide that links the phenylacetyl side chain to the ring nitrogen. Two effects compound in the same direction:

  1. Ring strain is relieved by reaction. A normal amide carbonyl carbon is sp2 and wants ~120° bond angles; forcing it into a four-membered ring compresses those angles toward 90°, raising the ground-state energy substantially. Any nucleophilic attack at that carbonyl (the first step of hydrolysis or of acylating a bacterial enzyme) moves the carbon toward sp3 (tetrahedral intermediate), whose ideal angles are much closer to what the four-membered ring already imposes — so forming the tetrahedral intermediate relieves strain instead of costing extra energy, dramatically lowering the activation barrier relative to an unstrained (six-membered-ring or acyclic) amide.
  2. Amide resonance is largely switched off. A normal amide's low reactivity comes from N lone-pair donation into the C=O π* system (delocalising the nitrogen lone pair into the carbonyl, giving partial C–N double-bond character and a planar, resonance-stabilised arrangement). The bicyclic β-lactam's ring geometry prevents the nitrogen lone pair from achieving good orbital overlap with the carbonyl π system, so this resonance stabilisation is largely lost. With much less amide-resonance stabilisation, the β-lactam carbonyl behaves electronically more like a reactive ketone/ester than like a normal, unreactive amide.

Both effects make the β-lactam carbonyl unusually electrophilic and hydrolytically labile — which is precisely the chemistry that makes penicillins work as antibiotics: the strained, reactive β-lactam acylates (and permanently inactivates) the bacterial transpeptidase enzyme responsible for cross-linking the cell wall.