13- Lactam amide resonance

The higher frequencies of the /3-lactam carbonyl absorption in fused systems has been attributed to increased inhibition of amide resonance as the /3-lactam ring becomes less planar (b-72mI50900 p. 303). For the 3-cephems (61) there is also the possibility of enamine resonance which could further reduce the ability of the /3-lactam nitrogen to contribute to amide resonance. 

The role of IR spectroscopy in the early penicillin structure studies has been described (B-49MI51103) and the results of more recent work have been summarized (B-72MI51101). The most noteworthy aspect of a penicillin IR spectrum is the stretching frequency of the /3-lactam carbonyl, which comes at approximately 1780 cm" This is in contrast to a linear tertiary amide which absorbs at approximately 1650 cm and a /3-lactam which is not fused to another ring (e.g. benzyldethiopenicillin), which absorbs at approximately 1740 cm (the exact absorption frequency will, of course, depend upon the specific compound and technique of spectrum determination). The /3-lactam carbonyl absorptions of penicillin sulfoxides and sulfones occur at approximately 1805 and 1810 cm respectively. The high absorption frequency of the penicillin /3-lactam carbonyl is interpreted in terms of the increased double bond character of that bond as a consequence of decreased amide resonance, as discussed in the X-ray crystallographic section. Other aspects of the penicillin IR spectrum, e.g. the side chain amide absorptions at approximately 1680 and 1510 cm and the carboxylate absorption at approximately 1610 cm are as expected. 

Lactams are generally more reactive toward nucleophiles than are normal amides. The ease of the nucleophilic attack on the lactam carbonyl group is usually attributed to either relief of strain upon opening the ring [68], or to a reduction in the usual amide resonance due to nonplanarity of the bicyclic system [69]. However, the evidence to support unusual strain in the ring or reduced amide resonance in /3-lactam antibiotics is ambiguous. 

Some information concerning ring strain and amide resonance can be obtained by comparing monocyclic and bicyclic /3-lactams. Monocyclic /3-lac-tams are very resistant to alkaline and acid hydrolysis [70] [71] due to reso-... 

Fig. 5.5. Factors influencing the reactivity of the f-lactam bond a) amide resonance, and b) the nonplanar butterfly shape of penicillins...

Page demonstrated in 1992 in a critical analysis [73] that bicyclic /3-lac-tam antibiotics do not exhibit exceptional chemical reactivity. He concluded that neither kinetic nor ground-state effects indicate a significant degree of inhibition of amide resonance in penicillins and cephalosporins [72] [74], Indeed, in comparison to normal amides, the /3-lactam N-atom does not exhibit any enhanced ability to donate its electron pair to either protons or metal ions [75] [76],... 

The mechanism of acid hydrolysis is also different in acyclic amides and /1-lactams acid catalysis of acyclic amides proceeds via O-protonation (see Chapt. 4), whereas that of /1-lactams appears to be a unimolecular A1 type process, involving V-protonation (Fig. 5.6,b) [76], A-Protonation is not the result of reduced amide resonance but an intrinsic property of the /1-lactam structure, since bicyclic /1-lactams and monocyclic /1-lactams exhibit similar reactivity and behavior [76],... 

Much of the chemical reactivity of the /8-lactam antibiotics is associated with die /i-lactam moiety. The geometry and the accompanying increased ring strain results hr very little, if any. amide-resonance stabilization leading to a marked increase in chemical reactivity when compared to a normal amide. In fact, in many instances the reactivity of the lactam carbonyl is... 

In most cases, transformations at the C-7 position involve the /3-lactam ring opening due to the geometric strain it represents and its limited amide resonance . Except from a biological point of view, where the /3-lactam reactivity finds its interest (see Sections 2.03.5.2 and 2.03.12), it is mainly the nucleophilic attack that leads to opened carboxylic derivatives, as in the aminolysis shown in Scheme 16 <2006TL1737>. 

More recently, Doyle has shown that even an acyclic amide such as (108) can cyclize smoothly to the 3-lactam (109 equation 38). -Lactam formation in these cases is surprising, since the electron-withdrawing heteroatom should direct insertion away from the a-C—H bond. It may be that in this situation, overlap between the filled orbital on the nitrogen atom and the C—H orbital can increase the electron density in the latter, thus making it more reactive. It may be pertinent that as (108) becomes more product-like, amide resonance decreases and the electron-donating ability of the nitrogen atom could... 

The structure of the penicillins (3.1) was established in the days before spectroscopic methods were routinely applied to structure determination. The degradative evidence for the structure of the penicillins is best understood if it is realized that the central carbon (C-5) of the thiazolidine ring in the core of the structure is a masked aldehyde and, secondly, that the p-lactam is a strained four-membered ring in which the lactam does not behave as a typical amide. The shape of the ring precludes the normal amide resonance and hence hydrolysis of the lactam takes place more easily than would be expected for an amide. This hydrolysis then places a carboxylic acid in the p-position to the masked aldehyde so that decarboxylation of a p-keto acid can occur. 

The striking difference in reactivity and stability of the 4//-l,3,4-thiadiazin-5(67/)-one (15 X = O) and the 5-ol (16) have been discussed in terms of resonance stabilization based on spectral data and extended Hiickel MO calculations <87NKZ1312>. The lactam exhibits typical amide resonance (15<- 15a) and is resistant to attack by electrophiles, nucleophiles, and free radicals, whereas the reactivity of the 5-ol (16) towards displacement of the hydroxy group by nucleophiles is attributed to resonance stabilization of the thiadiazinium cation (16a) formed by heterolysis of the C—OH bond. Extended Hiickel MO calculations on the thione analogue of the thiadiazinone, coupled with spectroscopic data, indicate that this system is best represented as the thione (15 X = S) <89CE797>. 

The data is generally in agreement with the expectations based on the sterics and structural distortions with the possible exception for the p-lactam where the calculations suggest higher amidicity for N,N-dimethyl-acetamide. Glover and coworkers report that p-lactams are essentially planar, and amide resonance in related monocyclic lactams is also efficient. ... 

The inefficiency of amide resonance in p-lactams and their spring-loaded reactivity associated with the release of angle and electronic strain played a defining role in the development of the key step in the Holton s synthesis of Taxol (Figure 11.58). ... 

Figure 11.58 Holton s synthesis of Taxol was assisted by the inefficiency of amide resonance in fi-lactams.

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