Passage
The β-lactam scaffold is an important feature in a class of broad-spectrum antibiotics that includes the penicillins, cephalosporins, and monobactams. These antibiotics are used to treat a variety of diseases caused by bacteria. The penicillins work by inhibiting a step in the synthesis of peptidoglycan. However, the development of antibiotic resistance in the form of enzymes such as β-lactamase is an ongoing problem.An aromatic ring linked to the β-lactam ring has been reported to participate in hydrophobic interactions with β-lactamase active sites, and an aromatic ring bonded to the nitrogen of the β-lactam has shown to be beneficial to biological activity. With this in mind, researchers synthesized a group of penicillanic acid analogues with substituted aromatic rings bonded to the β-lactam ring in an effort to overcome the challenge of antibiotic resistance. The substituents on the aromatic rings were varied, including -OCH₃ and -NO₂, to make several analogues. A key step in the synthesis of these analogues was the coupling of Compounds 1 and 2 to form a compound with two β-lactam rings (Reaction 1) .
Reaction 1The researchers studied the analogues' structure-activity relationship and antimicrobial activity against the gram-negative bacteria Escherichia coli and the gram-positive bacteria Staphylococcus aureus. Ampicillin, a penicillin derivative used to treat illnesses brought about by gram-positive and gram-negative bacteria, was used as a control. The minimal inhibitory concentrations are shown in Table 1.Table 1 Minimal Inhibitory Concentration (MIC)
The penicillanic acid analogues were tested for their effect on mammalian cell viability because toxicity to cells is also an important factor to consider for potential drug candidates. The general acceptable level of cell viability for a drug candidate is 70%. These results are shown in Figure 1.
Figure 1 Cell viability assay results
Adapted from De rosa M, Vigliotta G, Palma G, Saturnino C, Soriente A. Novel Penicillin-Type Analogues Bearing a Variable Substituted 2-Azetidinone Ring at Position 6: Synthesis and Biological Evaluation. Molecules. 2015.
-The precursor to Compounds 3-6 is shown below with carbonyl carbon atoms labeled. Which of the carbonyl carbon atoms is most likely to undergo hydrolysis when treated with a weak acid at room temperature?

Question

Passage
The β-lactam scaffold is an important feature in a class of broad-spectrum antibiotics that includes the penicillins, cephalosporins, and monobactams. These antibiotics are used to treat a variety of diseases caused by bacteria. The penicillins work by inhibiting a step in the synthesis of peptidoglycan. However, the development of antibiotic resistance in the form of enzymes such as β-lactamase is an ongoing problem.An aromatic ring linked to the β-lactam ring has been reported to participate in hydrophobic interactions with β-lactamase active sites, and an aromatic ring bonded to the nitrogen of the β-lactam has shown to be beneficial to biological activity. With this in mind, researchers synthesized a group of penicillanic acid analogues with substituted aromatic rings bonded to the β-lactam ring in an effort to overcome the challenge of antibiotic resistance. The substituents on the aromatic rings were varied, including -OCH₃ and -NO₂, to make several analogues. A key step in the synthesis of these analogues was the coupling of Compounds 1 and 2 to form a compound with two β-lactam rings (Reaction 1) .

Reaction 1The researchers studied the analogues' structure-activity relationship and antimicrobial activity against the gram-negative bacteria Escherichia coli and the gram-positive bacteria Staphylococcus aureus. Ampicillin, a penicillin derivative used to treat illnesses brought about by gram-positive and gram-negative bacteria, was used as a control. The minimal inhibitory concentrations are shown in Table 1.Table 1 Minimal Inhibitory Concentration (MIC)

The penicillanic acid analogues were tested for their effect on mammalian cell viability because toxicity to cells is also an important factor to consider for potential drug candidates. The general acceptable level of cell viability for a drug candidate is 70%. These results are shown in Figure 1.

Figure 1 Cell viability assay results
Adapted from De rosa M, Vigliotta G, Palma G, Saturnino C, Soriente A. Novel Penicillin-Type Analogues Bearing a Variable Substituted 2-Azetidinone Ring at Position 6: Synthesis and Biological Evaluation. Molecules. 2015.
-The precursor to Compounds 3-6 is shown below with carbonyl carbon atoms labeled.

Which of the carbonyl carbon atoms is most likely to undergo hydrolysis when treated with a weak acid at room temperature?

Quizplus · Accepted Answer

11ecba2d_126f_e413_a3bf_9947bb79a35e_MD0008_00 Carbonyls are made of a carbon atom double-bonded to oxygen and single-bonded to two R groups. The carbon atom is an electrophile because the carbonyl oxygen draws electrons away from the carbonyl carbon atom, creating a partial positive charge on the carbon. Carbonyls have varying reactivity based on whether the R groups are electron donating (EDG) or electron withdrawing groups (EWG). Electron donating atoms increase the electron density around carbonyl carbons, making them less electrophilic and therefore less reactive. Electron withdrawing atoms increase the electrophilicity and reactivity of carbonyl carbons by pulling electron density away from them, increasing their partial positive charge. The hydrolysis of carboxylic acid derivatives forms a carboxylic acid and another molecule, which depends on the derivative being hydrolyzed. Esters and amides can both undergo hydrolysis via nucleophilic substitution to form alcohols and amines, respectively. However, due to carbonyl reactivity differences, different conditions are required for hydrolysis. The precursor to compounds 3-6 contains two different carbonyl groups: an ester (carbon 4) and three amides (carbons 1-3). The electron withdrawing oxygen of an ester makes the carbonyl more electrophilic and reactive whereas the electron donating nitrogen of an amide makes the carbon atom less reactive and electrophilic. Because an ester is more reactive, milder conditions (weak acid and room temperature) are sufficient for it to undergo hydrolysis. (Choices A, B, and C) Carbons 1-3 are all amides, and carbons 1 and 3 are cyclic amides known as lactams. Amides are more stable and less reactive than esters because they contain an electron donating nitrogen atom. Therefore, amides require harsh conditions (strong acid or strong base and heat) to undergo hydrolysis. Educational objective: Carbonyls are electrophiles whose reactivity depends on whether an electron donating or electron withdrawing atom is bonded to the carbonyl carbon. Electron donating atoms decrease reactivity and increase the electron density around carbonyl carbons whereas electron withdrawing atoms increase reactivity and decrease the electron density around carbonyl carbons. More reactive carboxylic acid derivatives can hydrolyze under mild conditions whereas less reactive derivatives require harsh conditions.

Passage The β-Lactam Scaffold Is an Important Feature in a Class