Several naturally occurring penicillins have now been isolated, and numerous derivatives of these substances have been synthetically produced. All have structures containing a four-membered β-lactam ring (4 membered cyclic amide) fused with a five-membered thiozolidine ring. The carbon atom of the amide on the β-lactam ring can be bonded to any substituent, called the ‘R-group’. Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by three fundamental structural requirements: the fused beta-lactam structure (shown in the blue and red rings, a free carboxyl acid group (shown in red bottom right Figure1.1), and one or more substituted amino acid side chains (shown in black).
The lactam structure can also be viewed as the covalent bonding of pieces of two amino acids – cysteine (blue) and valine (red).
Fig. 1.1: Penicillin – Beta Lactam Structure
In terms of functional groups, the penicillin has 4 different functional groups: namely, carboxylic group, amide group, methyl group, and thioether group. Penicillin consists of many different functional groups but as a group of drugs the difference lies in the group that is placed after the unified functional group called a penam. The penam is a characteristic feature of the Penicillin family of drugs. A penam group contains a ketone with one R group consisting of a secondary amine. This secondary amine bridges the ketone to the Beta-lactam ring that is a four membered ring with nitrogen bonded to a carbonyl group.
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That ring is attached to another ring that is considered a cyclopentyl-thioether that is a cyclic ether with a sulfur atom instead of an oxygen atom. The last functional group is the Carboxylic acid, which is a carbonyl group bonded to an alcohol group. The beta-lactam ring and the cyclic thioether are, collectively, also considered a bicyclic compound. One can see that the lactam ring is highly strained: four near 90o angles create an instability that can only be relieved by an acid-catalyzed opening of the ring.
This is one feature of the β-lactam ring that gives rise to its acid sensitivity. Another important aspect of the lactam ring is the lack of resonance of the amide bond. A carbonyl-tertiary amide bond is usually stabilized by resonance: the nitrogen is able to ”turn over” and feed its lone pair of electrons into the electrophilic carbonyl group (Figure 2).
This stabilization reduces the electrophilic character of the carbonyl group, thusly providing a more stable carbonyl-amide bond.
Fig. 2: Resonance structures of a carbonyl group bonded to a tertiary amide.
However, the bicyclic structure of penicillin forbids this resonance strictly by mechanics. The nitrogen cannot turn over to donate its electrons, as this would require the thiazolidine ring to become co-planar with the lactam ring, forming an impossibly strained flat bicyclic structure (Figure 3).
Thus, the nitrogen retains its lone pair of electrons, and the carbonyl is left to be very electrophilic; – a situation that allows for the acid-catalyzed decomposition of penicillin, i.e., the opening of the b-lactam ring.
The Review on Group Cohesiveness
We are thankful to a lot of people for all the cooperation and support they extended, without which this project would not have been possible. We are grateful to our Organizational Behaviour – II Professor Manish Singhal, for giving us the opportunity to work on this project, and for all his guidance in his course lectures. We are thankful to our teaching assistants Gaurav Marathe and Madhu ...
Fig. 3: Impossible resonance of the lactam ring.
The stereochemistry along the lactam ring is required of a penicillin, as well as the carboxyl group on the thiazolidine ring. The sulfur atom on this ring has been substituted in certain studies, but is kept present for the molecule to be classified as a penicillin. The acyl-amino side chain is required, but the R-group can be varied.
Because the R-group is the only variable component of the molecule , the identity of a penicillin molecule is dependent entirely upon the chemical make-up of R. Therefore, the variation of the R-group is key in making semi-synthetic penicillin analogues. These chemical analogues vary in their acid sensitivity, bacterial resistance, and efficacy against certain types of bacteria.
