Nitrogen-Containing Molecules

41. Consider the case of N-(tert-butyl)-N-neopentylbenzylamine (shown to the right). According to a recent article, "The anti arrangement of the t-BuNCH₂-t-Bu part of the molecule greatly limits the space available for the benzyl substituent, and only one conformation about the N-benzyl bond is populated. Molecular mechanics calculations suggest that the benzyl group occupies a pocket or cleft ... " The assignment here is to confirm or disprove the preceding assertion and to examine other tertiary amines of the type PhCH₂-N-(t-alkyl)(CH₂-t- alkyl).

[Anderson, J. E.; Tocher, D. A.; Casarini, D.; Lunazzi, L. J. Org. Chem. 1991, 56, 1731;
Anderson, J. E.; Casarini, D.; Lunazzi, L. J. Chem. Soc., Perkin Trans. 2 1991, 1431.]

47. Ammonia has a nearly perfect tetrahedral shape with a 107° angle between any pair of H-N bonds. It is alleged that highly crowded amines flatten out, such that the bond angles approach 120°. Use MM to calculate the geometry of R₃N: where R = CH₃ or CH₂CH₃ or CH(CH₃)₂ or C(CH₃)₃. Compare your answers with the calculated and experimental values for triisopropylamine in the cited article; also compare with the analogous series R₃O:⁺ and R₃C-H where, again, R can vary from methyl to t-butyl.

[Bock, H.; Goebel, I.; Havlas, Z.; Liedle, S.; Oberhammer, S. Angew. Chem., Int. Ed. Engl. 1991 30, 187.]

96. Intramolecular aza Diels-Alder reaction gave exclusively one stereoisomeric product. The relative configuration at the three stereogenic centers was determined by ¹H-NMR vicinal coupling constants. For three stereogenic centers, there are (of course) eight possible stereoisomers; do MM calculations on four of these (keeping the H at C_9a down, for example, and varying the configurations at C₈ and C₂. Calculate relative energies and vicinal coupling constants; compare your results with the calculated and experimental results in the cited article.

[Uyehara, T.; Chiba, N.; Suzuki, I.; Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4371.]

137. The S-(-) tertiary amine to the right (and related compounds, see reference) serve as models for various cationic intermediates in the biosynthesis of certain terpenoids. As such, they are potential inhibitors of the enzymes which catalyze cyclization. Use MMX to calculate the geometry and energy of the important conformations of this compound; compare your answers with those in Fig. 3 of the article.

[Cane, D. E.; Yang, G.; Coates, R. M.; Pyun, H.; Hohn, T. M. J. Org. Chem. 1992, 57, 3454.]

155. Do a complete conformational analysis on isopropyldimethylamine. Calculate the energy and structural parameters (angles, dihedral angles, distances) of the stable staggered conformations (about the central C-N bond); use the dihedral driver to calculate the barrier to rotation between the conformations called GA and AG in the article as well as between conformations AG and GG. Compare your results with the experimental and calculated results in the reference.

[Brown, J. H.; Bushweller, C. H. J. Am. Chem. Soc. 1992, 114, 8153.]

170. A new synthesis has led to a mixture of all four diastereoisomers of octahydronaphthoquinolzidine. Do MMX calculations on the energy and structure of all of the isomers. Discuss those structural factors that lead to the differences in stability.

[Cai, B.; Pan, Y.; Dewan, J. C.; Wink, D. J.; Murphy, R. B.; Schuster, D. I. Tetrahedron Lett. 1993, 34, 2067.]

171. The bicyclic compound to the right not only has a bridgehead C=C but, if one considers normal amide resonance, a bridgehead N=C bond as well. Do MMX calculations on the series n = 2, 3, and 4. Compare the bond lengths and key dihedral angles with both the experimental and calculated values in the article; comment on the importance of amide resonance in such compounds.

[Lease, T. G.; Shea, K. J. J. Am. Chem. Soc. 1993, 115, 2248.]

179. Trimerization of 1-azacyclohexene or 1-azacyclopentene gives, respectively, the structures to the right. For each, compute the relative energies of the various conformations; the stereochemistry is fixed, of course, at the carbon centers but may invert at one or more of the nitrogen centers. Compare your results with those in Table XII in the cited reference.

[Wiberg, K. B.; Nakaji, D. Y.; Morgan, K. M. J. Am. Chem. Soc. 1993, 115, 3527.]

180. Do MMX calculations on the 1-alkyl-2,2,6,6- tetramethylpiperidines and on their cyclohexane analogs. Let the alkyl group be ethyl in one pair, neopentyl in the other. Determine the bond lengths, angles, and dihedral angles and compare them with those in Tables I and II in the reference. Do you agree that the preferred conformation in some of these cases has eclipsed rather than staggered bonds?

[Anderson, J. E.; Tocher, D. A.; Corrie, J. E. T.; Lunazzi, L. J. Am. Chem. Soc., 1993, 115, 3494; see also Anderson, J. E.; Casarini, D.; Corrie, J. E. T.; Lunazzi, L. J. Chem. Soc., Perkin Trans. 2 1993, 1299.]

194. Like cyclohexanes, the hexahydropyrimidines can have N-substituents axial or equatorial. Do MMX calculations on the three structures for R = CH₃ and compare your energy estimates with those in the reference. Then let R,R be a bridging (CH₂)_x chain; for x = 3, confirm that only the axial/axial structure is possible. Estimate what x must be for structures having axial/equatorial or equatorial/equatorial to exist; compare your answers with those in the reference.

[Alder, R. W.; Heilbronner, E.; Honneger, E.; McEwen, A. B.; Moss, R. E.; Olefirowicz, E.; Petillo, P. A.; Sessions, R. B.; Weisman, G. R.; White, J. M.; Yang, Z.-Z. J. Am. Chem. Soc. 1993, 115, 6580.]

206. Condensation of the bispyrimidine (to the right) with formaldehyde gave a product whose NMR spectrum did not permit a decisive choice between the two structures shown. Do MMX calculations on both of these products in their several available conformations (i.e., not only can the ring do its chair/chair interconversion but there is epimerization possible at the ring N's). Compare your results with those in the cited article.

[Kassiou, M.; Read, R. W. Tetrahedron 1994, 50, 2497.]

218. Caprolactam (shown to the right), despite its having a seven-membered ring, is conformationally quite similar to cyclohexane. That is, the amide group (which is constrained to be planar) acts like a very large CH₂ group, allowing chair and twist conformations to exist. First, convince yourselves that the chair and twist of the parent compound resemble those of cyclohexane. Then, do MMX calculations (four total) on the 7-t-butyl derivative with the group axial or equatorial in the chair and axial or equatorial in the twist. Do the same for the four possible 3-t-butyl structures. Compare your results with those in the article and with what you'd expect (based on cyclohexane) for energy differences in chair vs. twist and in equatorial vs. axial t-butyl.

[Matallana, A.; Kruger, A. W.; Kingsbury, C. A. J. Org. Chem. 1994, 59, 3021.]

233. Base catalysis leads to epimerization at the position that is alpha to the carbonyl in the system on the next page. Do MMX calculations on both double-chair conformations of each of these two epimers. [Note that when chair inversion occurs, the methyl on N does not interconvert between equatorial and axial; rather, it remains equatorial because of rapid inversion at N.] Compare your determination of "most stable" species with that given in the cited reference (in which the ethyl group is replaced by propyl).

[Naruse, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994, 35, 9213.]

240. Shown to the right are three stereoisomers of perhydropyrene; the first two have trans fusions at the central bond, whereas the third has a cis-fused system. Compute the MMX structures and energies of these isomers and compare your values with those in the cited article. Then, replace all four C-H groups at letters a ... d with N atoms having a lone pair of electrons and re-do the calculation; compare your results with those in the reference.

[Okawara, T.; Takaishi, H.; Okamoto, Y.; Yamasaki, T.; Furukawa, M. Heterocycles 1995, 41, 1023.]

243. Acid-catalzyed cyclization of an acyclic precursor (R = (CH₂)₅OTBDPS) produces the pair of stereoisomeric oxaquinolizidines shown to the right. Do MMX calculations on the simpler model compounds with R = CH₃. For each of these stereoisomers, keep the CH₂OH group equatorial, but recognize that inversion at the bridgehead nitrogen permits one conformation that resembles cis-decalin, another that resembles trans-decalin. Compare your calculated energies with those for the various methods of molecular mechanics shown in Table 2 in the cited reference.

[Börjesson, L.; Csöregh, I.; Welch, C. J. J. Org. Chem. 1995, 60, 2989.]

245. N,N-dimethyl-1,6-diazacyclodeca-3,6-diyne (shown to the right) can exist in a chair-like or a boat-like conformation. Do MMX calculations on both conformations; ascertain their relative stability; and determine whether the C-C-C bond angle is the ideal 180°. Although only the boat conformation can be used as a spacer in the meta-cyclophane (also to the right), there is still the question of whether the N-CH₂Ar bonds are axial or equatorial; do MMX calculations to resolve this.

[Gleiter, R.; Hövermann, K.; Ritter, J.; Nuber, B. Angew. Chem., Int. Ed. Engl. 1995, 34, 789.]

249. The complete conformational analysis of 2-(diethylamino)propane is complicated because there are some ten staggered conformations corresponding to rotation about the three C-N bonds. Of all of these conformations, two are considerably more stable (see Scheme 1 and Table 7 in the cited reference). Do calculations of the energies and geometric parameters of these two conformations (and of any others that you care to look at); compare your results with those in the article; decide which factor(s) are most important in determining the conformational energies.

[Brown, J. H.; Bushweller, C. H. J. Am. Chem. Soc. 1995, 117, 12567.]

261. The dioxa-tetraaza-substituted derivative of perhydroanthracene (shown to the right) has recently been made. Although the authors of the article considered only three structures for doing their calculations, you should do MMX calculations on all of the structures that correspond to the five stereoisomeric perhydroanthracenes discussed in Chem. 550. That is, consider each N with its lone pair as equivalent to a C-H of the parent hydrocarbon. Compare your energy calculations with those for the related perhydroanthracenes.

[Okawara, T.; Ehara, S.; Kagotani, H.; Okamoto, Y.; Eto, M.; Harano, K.; Yamasaki, T.; Furukawa, M. J. Org. Chem. 1996, 61, 4125.]

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