Oxygen-Containing Molecules

31. Do a complete MM analysis of the trans-1,2-disubstituted compounds shown to the right in which Z is SCH₃ (if you wish, you can also do Z = SOCH₃ or SO₂CH₃) and in which Y can be OH, OCH₃, F, Cl, Br, or I.

36. There are six reasonable conformations for the molecule shown to the right. All six are shown in the article cited below. Calculate the relative energies of these six conformations and compare your numbers with those obtained by the authors (using a somewhat different molecular mechanics calculation than MMX). Use molecular models to help you see the characteristics of the conformations.

50. The heats of reduction of a series of carbonyl compounds (aldehydes and ketones) to the corresponding alcohols have been measured; from these, the heats of formation of the oxidized and reduced species have been determined. Use molecular mechanics to compute the heats of formation of (a) aldehydes ethanal, propanal, butanal, and 2- methylpropanal; (b) ketones acetone and the five cycloalkanones from the 4- through the 8-membered rings; and (c) the alcohol reduction products. Compare your answers with the experimental values and the computed MM3 values cited in the article.

82. Starting in late 1989, Allinger has published a series of articles on MM3, a new version of molecular mechanics with a new force field and new parameters. The most recent article concerns calculations on various aldehydes and ketones. Suitable projects would be: (a) calculate the energies and structures of the conformations of methyisopropyl ketone and of diisopropyl ketone and compare the results with those in Tables XII and XIII; (b) calculate the energies and structures of the important conformations of cyclopentanone, cyclohexanone, and cycloheptanone (Tables XVI, XVII, and XX); (c) calculate the energies of the several conformations and stereoisomers of cis and trans "dimethyl decalin-1,4-dione" (Table XXVII); (d) calculate the energies of various other aldehydes and ketones for comparison with the experimental heats of formations in Tables XXX- XXXII).

85. In order to understand the stereo- and regiochemical aspects of various cyclization steps used for synthesis, MMX calculations were performed on the cis-2-oxabicyclo[4.n.0] compounds where n = 4 or 3 or 2. For all three of these compounds, do MMX calculations on the equilibrating chair conformations of the six-membered ring; evaluate boat conformations where necessary. Compare your results with those shown in Figures 4 and 5 of the reference. Decide which factors are important in determining the energy differences between conformations.

93. In experiments designed to elucidate the stereochemistry of [1,3] sigmatropic carbon shifts, the trideuterio-substituted vinylcyclopropane (see below) was pyrolyzed; migration of C₅ (or C₄) from C₃ to C₁, with concomitant reorganization of the pi electrons, produces the substituted cyclopentene (numbered so as to agree with the carbon numbers in the reactant). In order to determine the relative stereochemistry of the deuterium-labeled carbons, the alkene was epoxided, giving a mixture of epoxides (50% from above the plane, 50% from below); ¹H-NMR spectroscopy was used to assign stereochemistry. Your tasks are: (a) to confirm or disprove the authors' assertion that this epoxide exists preferentially in a boat rather than in a chair conformation; (b) to decide if this boat preference is or is not caused by the t-butyl group (i.e., do MM calculations on cyclopentenoxide itself); (c) to use MM to determine all of the vicinal coupling constants (between H's on C₁ and C₅, and between H's on C₅ and C₄) in the two product epoxides and to compare these with the experimental values cited in the paper; (d) to decide if the authors were justified in the relative stereochemistry which they assigned to the three stereogenic centers. [Do your calculations of energy and of J values on the non-deuteriated cyclopentenoxides.]

97. Consider the series of lactones, n = 3 through n = 8. Do MM calculations on the heats of formation, stable conformations, bond distances, bond angles, dihedral angles, etc. Compare your results with the experimental and theoretical results (Tables VI and VIII, Figures 1 and 2) of the cited reference.

102. For bicyclo[5.2.1]decane-2,6-dione (shown to the right), there are five reasonable conformations; see the cited reference for the names and structures of them. Do MM calculations of their energies, and compare these with the experimental and calculated values in the article.

107. Calculate the conformational energies of the relatively stable conformations of oxocane (C₇H₁₄O) and compare your results with those in the cited reference (Table I). Do your calculations on the conformations called BC-1, BC-3, BC-4, TBC-1, and TCC-1 (those which are within 2 kcal/mol of each other). If desired, you can then use the dihedral driver program to try to reproduce the barriers to conformational change in Table II.

115.

Naturally occurring bicyclic ene-diynes (general structure shown above) cyclize thermally. In a recent article, the scope of this reaction was measured as a function of bridge length n and of substituents at positions a and b. The observed rates correlated quite well with the energies computed for various simple models for the cyclization product. The essence of this MMX problem is to compute the structures and energies of model compounds 1 and 2 (n = 1, 0), 3 and 4 (n = 1, 0), and 5 (to the right). Use the differences in strain energies to confirm or disprove the conclusions drawn on p. 2554-5 of the cited reference.

120. E,E-Suspensolide, the 11-membered lactone with two E double bonds shown to the right, is a major component of the sex pheromone of the Mexican fruit fly. Really! There are four reasonably stable conformations (see Scheme I in the cited article) available for this compound. Use MMX to calculate the energies and structures of the four conformations; comment on similarities and differences between your calculations and those in the article.

122. The spiro-acetal (shown to the right) can exist in three favorable conformations: note that in 1, there are two axial C-O bonds; in 3, the two axial bonds are C-C; and in 2 there is an axial bond of each kind. Compute the MMX structures and energies of all three. Compare your relative energies with those in the cited reference; comment on the factors that lead to the wide range in energies for three such similar- looking structures. Then, do calculations on the related dimethyl-substituted acetal formed in the cyclization reaction. Note that there are two stereogenic centers; in fact, cyclization of racemic reactant gives a mixture of R,R + S,S + S,R cyclic products, each one of which can exist in conformations like 1, 2, and 3. The interesting fact is that in one of the diastereomeric products, conformation 1 is preferred; in another it is 2; and in the third it is 3. Choose any one of the RR, SS, or SR compounds and do its complete conformational analysis in terms of structures 1, 2, and 3. [If you feel ambitious, do the calculations on all three diastereomers.] Compare your answers with those in the article.

133. Do a complete conformational analysis of both stereoisomers (cis and trans) of the system to the right. For each isomer, calculate the energy and key dihedral angles for four different conformations: i.e., the TMS and ester groups can be axial or equatorial and the ring oxygen can be syn or anti to the TMS. Compare your answers with those in the cited reference. Discuss similarities and differences.

135. This is a problem reminiscent of number 126. For the anthracenones (shown to the right), calculate the extent of non-planarity of the central ring as R varies over the series H, Me, Et, iPr, tBu. Use the measures of nonplanarity suggested in Table I (and the accompanying discussion). Compare your results with those of the cited reference. Discuss similarities and differences.

136. Furans are relatively poor Diels-Alder dienes, and never add to unactivated double bonds. Nevertheless, intramolecular versions of this reaction are known (as shown to the right). Using MMX, calculate the energies and geometric parameters of both reactant and product in four isomeric systems: m = 2, n = 2, double bond E or Z; and m = 1, n = 3, double bond E or Z. Compare your answers with those in footnote (22) of the cited reference. Comment on whether your calculations help in understanding why some of these cyclizations occur but others don't.

139. For the dispiro compound to the right, there are two distinct stereoisomers: one has the two oxygens cis; the other has them trans. For the trispiro compound, there are three distinct stereoisomers. All of these isomers, of course, are conformationally mobile. Calculate the relative energies of each chair and its inverted conformation in order to determine where the conformational equilibrium lies; compare your answers with those which have been established experimentally.

141. Problem 82 concerned the application of the new MM3 to aldehydes and ketones. In a more recent paper, MM3 calculations have been done on carboxylic acids, esters, and lactones. A reasonable project would be to run MMX calculations (and to compare the results with MM3) on structural parameters (Tables II - VIII), dipole moments (Table XI), and heats of formation (Tables XXII and XXIII) for a series of acids, esters, and cyclic esters.

142. The bicyclic unsaturated ketone, synthesized by an intramolecular Diels-Alder reaction, serves as a model for Taxol. Enolate formation followed by methylation leads either to alkylation at the bridgehead position or at the alternative alpha-position. The authors argue that the bridgehead enolate is formed faster, but that the other enolate is more stable; hence, the proper choice of strong base can control the direction of enolization. This MMX problem consists of two parts: (1) calculate the geometrical parameters of the starting ketone to see if you agree with the authors that the bridgehead proton is removed fastest; (2) calculate the energies of the neutral enols corresponding to the two enolates shown and of the third possible enolate (the geometric isomer of the right-hand structure) to determine which is the most stable.

169. There is evidence that the preferred conformation for an equatorial methoxy group has the H_ax-C-O-Me dihedral angle eclipsed (or nearly so) rather than anti. Do MMX calculations on trans,trans-1,2,3-trimethoxycyclohexane in its all-equatorial conformation. Calculate energies and dihedral angles for the various combinations of eclipsed and anti conformations. Discuss the factors that lead to the different energies.

178. A recent article describes the use of a [2,3]-Wittig reaction for the stereospecific synthesis of a target molecule. Shown to the right are two chair conformations that are used to model the reactive intermediate in the Wittig; in the actual reaction, the ether substituent is an organometallic O-CH₂-Li. The conformation on the left, although preferred, does not have the correct orbital orientation for the rearrangement, whereas the one on the right does have the correct orientation but is very unstable. Use MMX calculations to get the relative energies of these two chairs and of the two relatively good twist conformations in equilibrium with them - decide if the authors are correct in asserting that one of the twists is actually more stable than the unstable chair. Then, although this wasn't done in the article, change the configuration of the double bond from E to Z and re-do the calculations for the two chairs and two twists; see if you get the "surprising" result that the seemingly preferred chair is actually less stable than both the other chair and the two twists!

182. Shown to the right is the framework of the cis-eudesm-11-en-4-ols for which there are four possible stereoisomers. For each stereoisomer, compute the relative energies of the two equilibrating double-chair conformations. Compare your results with those reported in the article. Do you agree that three of these isomers are essentially 100% in a single conformation, but that one isomer has appreciable amounts of both conformations at equilibrium?

204. Spiro heterocyclic rings have been introduced at C₂ and C₃ of cyclohexanone. The heteroatoms X and Y can be either syn or anti. Choose either the syn or anti series and do calculations of the two chair conformations for the four compounds X=Y=O; X=S,Y=O; X=O,Y=S; and X=Y=S. Discuss the position of conformational equilbrium in terms of axial and equatorial groups. Compare your results with those in the cited reference.

226. There are two isomers, cis and trans, for 1,3,5,7-tetraoxadecalin. Use MMX to calculate the relative energies of the cis and trans isomers as well as the relative energies of the two conformations for the cis. The results will be very different from what is found for cis- and trans-decalin. Discuss these differences in terms of structural differences; use the cited references as a guide; ascertain whether the same effects pertain to the stereoisomers of 1,4,5,8- tetraoxadecalin.

228. Consider the conformational equilibrium shown to the right. In a recent article, it is alleged that the equilibrium lies on the side of the diequatorial conformation for R = methyl but on the side of the diaxial for R = isopropyl. Do calculations on both conformations of these two compounds and on other trans- 2,3-dialklyl-1,4-dithianes of your choosing; discuss the effect of size of the alkyl group on which conformation is preferred.

232. Methoxycyclohexane, shown to the right in its equatorial conformation, has "free rotation" about the C₁-O bond. Calculate the dihedral angle H-C₁-O-CH₃ for equatorial methoxy and for its derivatives with equatorial 2-methyl and with diequatorial 2,6-dimethyl groups; do the same for axial methoxy and its mono- and di-methyl derivatives. Do you agree with the literature assertion that the dihedral angles are 0° in the dimethyl derivatives?

238. For the tetramethyl-[4.4]-para-cyclophane diketone shown to the right, there are various possible conformations. Do MMX calculations on the conformations shown in Fig. 2 in the cited article, and compare your computed energies with those obtained both by calculation and by experiment.

242. Base treatment of the conjugated tricyclic dienone (to the right) gives an equilibrium mixture of it and four isomers (two conjguated, two unconjugated). Do MMX calculations that will permit you to estimate the relative abundance of the five isomers at equilibrium. Compare your estimate with the experimentally determined values (cited in the reference).

253. The 1,3,5,7-tetraoxa derivatives of cis-decalin are mixtures of two rapidly interconverting conformations. In contrast to cis-decalin (for which K_eq = 1), these distal and proximal conformations are of unequal energy. Do MMX calculations on the parent system (R=R'=H), on the mono-methyl and mono-t-butyl systems (R=H, R'=Me or tBu), and on the dimethyl (R=R'=Me) system to see if substitution changes the position of equilibrium. Compare your results with the experimental and computed results in the cited reference.

252. A fascinating set of molecules called "starands" and "ketonands" have been the subject of synthetic efforts and calculations. Shown to the right is the equilibrium between the pair of compounds having four oxygens. According to the cited reference, the equilibrium lies on the side of ketonand for this case but on the side of the starand when there are six oxygens. Do MMX calculations on the [4]- and [6]-starands and on the [4]- and [6]- ketonands. Discuss the factors that are responsible for the direction of equilibrium. Compare your results with those in the reference.

258. The polyspiro tetrahydrofuranyl cyclohexanes shown to the right have recently been synthesized. Note that isomers 1 and 2 differ in stereochemistry only at C*. For each of these isomers, two chair conformations will be in equilibrium. By doing MMX calculations, decide for isomer 1 whether the conformation with four equatorial oxygens and two axial methylenes or the reverse is more stable; for isomer 2, decide whether is it better to have five equatorial oxygens and one axial methylene or the reverse. Identify the factors responsible for the energy differences.

260. Diels-Alder reaction of an enantiomerically pure unsaturated ketone (derived from D-(+)- glucose) with cyclopentadiene produces a structure with four new stereogenic carbons (identified by *). Because of constraints imposed by the rings, there are not 2⁴ isomers formed; rather, there are only four. Do MMX calculations on these. Compare your results with the experimental data concerning which of these isomers are actually produced.

262. Shown to the right is the conformational equilbrium for some substituted cyclohexanes. It was speculated that the equilibrium for the compound with X = COOH might lie to the left, especially since this would allow H-bonding between the carboxylic acids. It was further speculated that the equilibrium for the compound with X = COO- might lie to the right. Do MMX calculations to support or contradict these predictions; compare your results with the experimental and calculated results reported in the article.

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