Conformational analysis by nuclear magnetic resonance. Nitrogen-15 and carbon-13 spectra of lactams

Williamson, Kenneth L.; Roberts, John D.

doi:10.1021/ja00433a005

Cited by 79 publications

(32 citation statements)

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“…COSY and HETCOR correlations on both the unshifted and the most shifted spectrum were needed to assign the 1 H and 13 C spectra of N‐methyl‐ε‐caprolactam 3 . The assignment agreed with previous studies on ε‐caprolactam . In 1,5‐dimethyl‐2‐pyrrolidone 4 , the assignment techniques used gave an assignment in agreement with that of another reference, but this did not distinguish between the two protons bonded to C 4 .…”

Section: Methodssupporting

confidence: 72%

A theoretical and NMR lanthanide‐induced shift (LIS) investigation of the conformations of lactams.

Abraham

Filippi

Petrillo

et al. 2017

Magnetic Reson in Chemistry

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Molecular mechanics (MM) with MMFF94 and MMX force fields and ab initio (RHF/6-31G*,RHF/6-311G**, and B3LYP/6-311G**) calculations are used with lanthanide-induced shift (LIS) to investigate the conformations of N-methyl-2-pyrrolidone 1, N-methyl-2-piperidone 2, ε-caprolactam 3, γ-valerolactam (1,5-dimethyl-2-pyrrolidone) 4, 2-azetidinone 5, 4-methyl azetidinone 6, 4-phenyl azetidinone 7, and N-methyl-4-phenyl azetidinone 8. The Yb(fod) paramagnetic induced shifts of all the H and C nuclei are measured and the corresponding diamagnetic complexation shifts obtained by the addition of Lu(fod) . The complexation model (two-, three-, or four-site) used depends on the relative rates of the processes involved. The amide inversion is the same order as that of the 5- and 6-membered lactam rings and much faster than the lanthanide complexation and the inversion of the 7-membered ring. Both MM and ab initio calculations give an envelope conformation for 1 with C-4 out of the ring plane in agreement with the LIS analysis. For the piperidone ring of 2, the half-chair is calculated as the most stable form. The LIS analysis confirms this but cannot exclude a small amount (<2%) of the boat conformation. For 3, the LIS analysis gives a minimum for 90:10% chair to boat conformation, and 4 exists in two envelope conformations with the C -Me ps-eq and ps-ax in an eq/ax ratio of 94:6%. In 2-azetidinone 5, the ab initio calculations gave both ring and nitrogen planar, but the MMFF94 calculations give a butterfly ring and pyramidal nitrogen. The LIS analysis for 5 gave good agreement (Rcryst 0.46%) for the MMFF94 geometry with endo NH but the planar ab initio geometries worse agreement (Rcryst = 1.1%). For 4-methyl-2-azetidinone 6, the MMFF94 geometry gave good agreement (Rcryst 0.96%) with two butterfly conformations with axial and equatorial methyl groups in 1:1 ratio. All the planar geometries gave worse agreement (Rcryst >1.5%). In 4-phenyl azetidinone 7, the MMFF94 geometry with 60% of the axial conformer gave Rcryst 1.2% but the other geometries Rcryst >1.5%. In contrast the N-methyl-4-phenyl-2-azetidinone 8 gave good agreement for all the geometries. The butterfly conformation gave Rcryst 1.1% for 80% of the axial conformer and the planar geometries Rcryst 0.98%. The LIS results confirm the ab initio and MM optimised geometries, but the conformer energies at times differ from the calculated values. They also differ considerably from the corresponding values for the lactones studied previously, and possible reasons for this are discussed.

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Section: Methodssupporting

confidence: 72%

A theoretical and NMR lanthanide‐induced shift (LIS) investigation of the conformations of lactams.

Abraham

Filippi

Petrillo

et al. 2017

Magnetic Reson in Chemistry

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“…This is probably because spinning of the amide bond is discontinuous and also because the energy barrier of amide rotation is relatively high (~20 kcal/mol) 12–14 . Therefore, this observation suggested that the rotation of lactam amide is restricted 15–17 , and as a general trend, the amide bond in lactams cannot spin through 360 degrees, probably due to ring coiling (Fig. 1a).…”

Section: Introductionmentioning

confidence: 85%

Amide nitrogen pyramidalization changes lactam amide spinning

et al. 2019

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Although cis-trans lactam amide rotation is fundamentally important, it has been little studied, except for a report on peptide-based lactams. Here, we find a consistent relationship between the lactam amide cis/trans ratios and the rotation rates between the trans and cis lactam amides upon the lactam chain length of the stapling side-chain of two 7-azabicyclo[2.2.1]heptane bicyclic units, linked through a non-planar amide bond. That is, as the chain length increased, the rotational rate of trans to cis lactam amide was decreased, and consequently the trans ratio was increased. This chain length-dependency of the lactam amide isomerization and our simulation studies support the idea that the present lactam amides can spin through 360 degrees as in open-chain amides, due to the occurrence of nitrogen pyramidalization. The tilting direction of the pyramidal amide nitrogen atom of the bicyclic systems is synchronized with the direction of the semicircle-rotation of the amide.

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“…An advantage of '5N over 'H or '3C nuclear magnetic resonance spectroscopy for this purpose is that, with proton noise decoupling, only a single resonance line is expected for each aliphatic amino acid in the chain, provided there is exclusively a trans configuration or a cis configuration at each peptide bond. If multiple resonances were observed, this would be evidence for mixtures of cis and trans amino isomers (7).…”

Section: Methodsmentioning

confidence: 99%

Nitrogen-15 nuclear magnetic resonance of aliphatic tripeptides.

Markowski¹,

Posner²,

Loftus³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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The 15N chemical shifts of eight aliphatic tripeptides have been measured at the natural-abundance level. For a given tripeptide, the resonances of the COOH-terminal and NHlrterminal amino acids can be identified by measurements at low or high pH. The shifts of the NH~rterminal amino acid nitrogens are essentially independent of the amino acids in the rest of the peptide. The shifts of the other nitrogens are characteristic of the amino acids themselves and of the immediately preceding amino acid toward the NH2 terminus. Nonterminal amide nitrogens have shifts of about 6 ppm upfield of COOH-terminal amide nitrogens at the isoelectric point of measurement. 15N chemical shifts appear to have considerable potential value for peptide sequencing. Although carbon-13 nuclear magnetic resonance spectra can be used to distinguish between NH2-terminal, COOH-terminal, and nonterminal residues in small peptides (1, 2), the observed shifts are independent of the nature of the adjacent amino acid residue (3). For this reason, 13C chemical shifts are unable to provide much sequencing information for peptides containing more than three residues. In a recent communication (4), we have shown that resonance signals of nitrogen-15 are not subject to this limitation and show a distinct neighboring residuedependence for simple aliphatic dipeptides. The individuality of these shifts indicates that 15N nuclear magnetic resonance spectra might play a useful role as a nondestructive method for sequence analysis of peptides and, except for sensitivity problems, should be superior to 'H and '3C nuclear magnetic resonance spectroscopy. We provide here a further test of this expectation through studies of the 15N nuclear magnetic resonance spectra of some aliphatic tripeptides and also of dipeptides containing more complex amino acid residues than investigated earlier. EXPERIMENTAL SECTIONAll of the peptides were commercially available materials and were used without further purification. The spectra were taken of 0.1-0.2 M peptide solutions in water, and unless otherwise noted, the pH values were those of the isoelectric points. The spectra were recorded at 18.25 MHz on a Bruker WH-180 pulse spectrometer described in detail elsewhere (5). Reasonable signal-to-noise ratios could be obtained over 2-6 hr with the aid of proton noise decoupling, a 30 ltsec pulse width (300 flip angle), and a repetition rate of 2 sec. The chemical shifts reported are in ppm upfield from 1 M external D15NO3, which also was used as the external field-frequency lock.

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Conformational analysis by nuclear magnetic resonance. Nitrogen-15 and carbon-13 spectra of lactams

Cited by 79 publications

References 1 publication

A theoretical and NMR lanthanide‐induced shift (LIS) investigation of the conformations of lactams.

A theoretical and NMR lanthanide‐induced shift (LIS) investigation of the conformations of lactams.

Amide nitrogen pyramidalization changes lactam amide spinning

Nitrogen-15 nuclear magnetic resonance of aliphatic tripeptides.

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