Penams are the primary skeleton structures that define the

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...

subclass of the broader β-lactam family of

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...

and related compounds. They are bicyclic ring systems containing a β-lactam

moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...

fused with a five-member

thiazolidine Thiazolidine is a heterocyclic organic compound with the formula (CH2)3(NH)S. It is a 5-membered saturated ring with a thioether group and an amine group in the 1 and 3 positions. It is a sulfur analog of oxazolidine. Thiazolidine is a colorle ...

ring. Due to

ring strain In organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles are ...

and limitations on

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied periodic force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts. When an oscil ...

, the structure is unstable and highly susceptible to catalytic cleavage at the

amide bond In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

Benzylpenicillin Benzylpenicillin, also known as penicillin G (PenG) or BENPEN, and in military slang "Peanut Butter Shot" is an antibiotic used to treat a number of bacterial infections. This includes pneumonia, strep throat, syphilis, necrotizing enterocolitis ...

(penicillin G) is the natural product parent that contains the penam structure.

Structure and Bonding

Penams do not have flexible structures, due to their composition of rigid small rings. The four-membered ring and five-membered ring are not coplanar. Instead, the structure is locked in a puckered (i.e. bent) shape due to the pyramidal geometry of the bridgehead nitrogen. The pyramidalization (χ = 54°) and twist of the C-N bond (τ = 18°) is caused by the strain from the lone pair's exclusion from planarity with the cyclic rings and electrostatic repulsion effects. As a result, the distorted C-N bond causes misalignment the orbitals of the carbonyl carbon and the nitrogen lone pair that allow for resonance overlap. The amide C-N bond length is 1.406Å and displays greater single bond character than in noncyclic tertiary amides. The C-O bond length is 1.205Å which is shorter than C-O bonds in noncyclic tertiary amides.

Properties

Stability

Penam's overall thermodynamic stability is based on the summation of

destabilization effects (RSE) and

stabilization effects (ARE). Since the destabilization effects far outweigh the stabilization effects, penams are thermodynamically unstable and reactive to nucleophilic reactions that favor the cleavage of the β-lactam ring.

Ring Strain Effect

Penams are primarily destabilized because of the large angle and torsional strains that are associated with the four-member β-lactam ring, whose internal bond angles are 90º. Based on the similar strain energies observed in penams and standalone β-lactam rings, the fused five-member ring likely does not contribute to the overall strain effect unlike its six-membered ring counterpart in cephams which helped reduce ring strain. As a result, ring-opening reactions, e.g., hydrolysis, are thermodynamically favorable for their ring strain relief.

Amide Resonance Effect

Penams are stabilized by amide resonance effects. Unlike traditional tertiary amides which delocalize the nitrogen lone pair onto the carbonyl group's oxygen and result in double bond character at the C-N bond, the amide resonance in penam primarily occurs between the nitrogen and carbonyl carbon that's partially positive due to the inductive effect of the carbonyl oxygen. This is a result of the overlap interactions between the HOMO lone pair on nitrogen and the LUMO of the carbon. However, due to the pyramidalization of the nitrogen and the distorted C-N bond, the degree of amide resonance stabilization is lowered, with respect to planar amides such as the β-lactam moiety that have aligned orbitals for overlap.

Reactions

Penams are reactive towards catalytic cleavage via hydrolysis because of the carbonyl carbon's propensity for nucleophilic attack. This is understood by its partial positive (electrophilic) character that results from the

electron density In quantum chemistry, electron density or electronic density is the measure of the probability of an electron being present at an infinitesimal element of space surrounding any given point. It is a scalar quantity depending upon three spatial va ...

being slightly withdrawn by the carbonyl oxygen atom and, consequently, the lack of conjugation between the nitrogen and carbonyl group. Although

amide bonds In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 ( carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein ...

are typically unreactive to cleavage because of its partial double bond character, the pyramidalization and C-N bond distortion make the amide bond in penams have a single bond character, which is more reactive to cleavage. Also, cleavage of the C-N bond is thermodynamically favorable, since opening of the β-lactam ring reduces ring strain.

Catalyzed Cleavage

Ring-opening of penams can be acid- or base- catalyzed

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

. Under acidic conditions, the water acts as a nucleophile that attacks the electrophilic carbon of the carbonyl group. Under basic conditions, the hydroxide acts as the nucleophile. In

enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

, the hydroxyl group of a serine residue acts as the nucleophile. Regardless of which nucleophilic species that attacks the electrophilic carbon of the carbonyl group, the nucleophile binds, creating a tertiary carbon intermediate. Electrons are transferred from the C-N bond and onto the nitrogen atom which acts as the leaving group. As a result, the C-N bond is cleaved, forming a carboxylic acid and secondary amine.

References

{{Cell wall disruptive antibiotics Beta-lactamase inhibitors Sulfur heterocycles Nitrogen heterocycles Heterocyclic compounds with 2 rings Ketones