CHAPTER 8 SOLUTIONS TO EXERCISES

Transcription

1 CHAPTER 8 SOLUTIONS TO EXERCISES Solution 8.2. The walk starts with the anomeric proton (peak h), which can be unambiguously assigned because it is downfield of all the other peaks, and it is the only doublet. The dotted lines show the walk, from h to g, g to d, d to c, c to a, a to e and a to f. Peak f is correlated to peak e by the geminal coupling. The vicinal axial-equatorial couplings are small (0.9 and 3.2 Hz) and the axial-axial couplings are large (10.0 and 9.9 Hz), as is the geminal coupling (12.2 Hz). Solution 8.4. Methyl -6-deoxyglucoside. The walk begins with the anomeric proton (peak g) and proceeds to peak d, peak e, peak b, and peak f, and ends at peak a. Peak a is a methyl peak (integral 2.91) with an upfield shift (1.17 ppm) that rules out any bonds to oxygen. Peak c is a 8-1

2 methoxy group singlet, suggesting a glycosidic linkage to the sugar, consistent with the fact that there is only one anomer present. The small coupling of peak h (3.5 Hz) implies that the configuration is (anomeric proton equatorial). The H2 peak (peak d) has one large coupling (9.2 Hz) in addition to the coupling to H1 (peak h), so both H2 and H3 must be axial protons. Peak e (H3) is a 9.2 Hz triplet, so H4 must also be axial. Peak b (H4) also has two large couplings (t, J = 9.4 Hz), so H5 must be axial. With H2, H3, H4 and H5 all axial, the sugar stereochemistry is established as glucose. Since H1 is equatorial, we can say that it is -glucose. But H5 (peak f) is a double quartet (J = 9.6, 6.3 Hz), so the C6 position of the sugar has to be a methyl group, corresponding to peak a (d, J = 6.3 Hz). The sugar is 6-deoxyglucose, with a methyl glycoside and anomeric configuration. This exercise illustrates how the J coupling information can be put to work to quickly identify a sugar (i.e., establish relative stereochemistry), but this information is useless without peak assignments. The 2D COSY spectrum provides those assignments. The D or L specification (absolute stereochemistry) of a sugar cannot be established by NMR if the environment (solvent in this case) is achiral: enantiomers give identical NMR spectra. 8-2

3 Solution 8.6. Methyl -D-ribopyranoside. The 13 C data indicates a methoxy group (57.01 ppm), a CH2O (63.87), three singly-oxygenated CH-O carbons, and an anomeric CH carbon (103.14). Thus it is a 5-carbon aldose with a methoxy group. Since there is only one anomeric form present, the methoxy is probably in a glycosidic linkage. The ring size is given (pyranose), so the structure is established and only stereochemistry needs to be determined. The anomeric (H1) position is assigned to peak g (d, J = 5.1 Hz). Starting our walk at the peak g diagonal peak, we move to peak b (H2), then to peak f (H3), and peak e (H4). Peak e has correlations back to peak f (H3) and forward to peaks d and c (H5b and H5a). This completes the spin system. The vicinal J values divide into two groups: large (7.0, 5.1 Hz) and small (3.4, 3.4 and 3.6 Hz). Of the large couplings, the 5.1 Hz value is lower because it includes the anomeric proton (CH-CH with three bonds to oxygen). If we assume that the large couplings are axial-axial, the stereochemistry can be established starting with H1. Both H1 and H2 must be axial (large H1-H2 coupling), but H3 must be equatorial (small couplings to H3). H4 must be axial because it has a large coupling (7.0 Hz) to H5ax (peak c) and a small coupling (3.6 Hz) to H5eq (peak d). Peaks c and d form the AB portion of an ABX system, a common feature of CH2 groups in a chiral environment, and the large JAB (12.5 Hz) confirms a geminal relationship. The stereochemistry is similar to that of allose (an aldohexose with an equatorial CH2OH group in place of H6eq). The axial-axial J couplings in - allose are larger, similar to other aldohexoses: 8.5 Hz (H1-H2) and 9.5 Hz (H4-H5). The absence of an equatorial CH2OH group may change the conformation of the ring, or there may be conformational averaging due to significant populations of the other chair form. 8-3

4 Solution 8.8. The doublet peak near 5.50 ppm can be assigned to H1 (anomeric proton in the galactose-like unit), and the doublet peak at ppm can be assigned to H3 (proton in the fructose-like unit that is coupled only to H4 ). These are the only two protons in the molecule expected to give simple doublet peaks. The crosspeak at F1 = 4.13, F2 = can be assigned to H4, H3, while the crosspeak at F1 = 4.55, F2 = can be assigned to H4, H5. The former (H4, H3 ) is clearly centered farther to the left in the F2 = 4.40, 4.45 ppm gridline pair than the latter (H4, H5). The walk proceeds smoothly in both spin systems, given that the three upfield 2H peaks are an AB(X) system ( ppm), an AB system ( ppm) and a simple doublet (3.77 ppm). 8-4

5 Solution First the peaks in the 1D proton spectrum are labeled, starting at the upfield end (expansion 1). The first peak ( ppm, integral 5H) has a tall methyl doublet in the center (3H), which gives a double streak of t1 noise extending down from the diagonal in expansion 2. In the bottom part of this streak there are two crosspeaks, one with a center slightly to the right of the streaks, and one with a center slightly to the left. These are due to one-proton peaks in F2, one slightly upfield of the methyl doublet and one slightly downfield. These three peaks can be labelled a, b and c. Peaks d and e are single-proton (resolved) peaks, and then we come to an overlapped peak at ppm (integral 5H). At the left edge of this overlap is a tall methyl singlet-like peak ( S ), leaving 2H for the ppm region. Following this F2 region to the bottom of COSY expansion 2, we come to two crosspeaks at the bottom that are slightly offset in F2. The one on the right can be labelled peak f in F2, the one on the left peak g, and the methyl peak can be labelled peak h. Next we encounter two more resolved peaks, peak i (~ 1.88 ppm) and peak j (~ 2.04 ppm). Continuing in the vertical 1D trace of expansion 1, we have peak k (H- C-O, ~ 3.47 ppm) and the two olefinic protons (H-C=C, ~4.85 and 4.90 ppm) labelled peaks l and m. In the 2D spectra shown below, the letter labels (a, b, c ) are used on the 1D traces (F1 and F2) and structural numbering (2, 6ax, 8t, etc.) is used to label the crosspeaks. In expansion 1, the crosspeak at the bottom connects the two olefinic proton peaks (peaks l and m, near 4.9 ppm) to the methyl peak (peak h, ~ 1.71 ppm), through allylic ( 4 J) couplings. Peaks l and 8-5

6 m can be assigned to the geminal pair on C8, and the singlet-like ( S ) peak h is assigned to the methyl protons on C9. Peak k (near 3.47 ppm) can be assigned to H1 because of its chemical shift (H-C-O, generic shift 3-4 ppm). It has crosspeaks to peaks j, i and c, which correspond to the three protons on C2 and C6 (vicinal couplings to H1). In expansion 2 there is a crosspeak between peaks c and j (upper left corner and lower right corner), but no crosspeaks from either of these two peaks to peak i. This proves that peaks c and j are the geminal pair on C6, and peak i can be assigned to H2. The relative downfield shift, narrower footprint and doublet-like appearance ( D ) of peak j establishes that it is H6eq, and peak c can be assigned to H6ax. The other methyl group, C10, must be the off-scale doublet near 0.95 ppm (peak b), which gives two vertical streaks of t1 noise extending down from the diagonal peak. A narrow crosspeak can be seen in this streak at an F1 shift near 1.5 ppm, and the symmetry-related crosspeak at F2 ~ 1.5 ppm (center top of expansion 2) is much clearer, connecting the peak b methyl group to peak e. Peak e can be assigned to H5; the very wide footprint and complex splitting pattern are due to the 7 neighbor (vicinal) protons around H5. Peak e (H5) has a weak crosspeak to peak j (H6eq). Because of its many coupling partners, peak e is low and wide in the 1D spectrum and it gives weak crosspeaks in the 2D COSY spectrum. Returning to peak i (H2, ~1.88 ppm) on the diagonal, moving right there are two crosspeaks connecting it to peak g (the downfield side of the overlapped pair at ppm) and peak d. The crosspeak at F1 ~ 1.88 ppm (peak i), F2 ~ 1.67 ppm (peak g) is clearly to the left of the crosspeak below it (F2 = peak f). This very subtle distinction is important since peaks f and g have almost the same chemical shift. The footprint of peak d is larger than that of peak g (using the width of crosspeaks in F2, or the height in F1, to compare) and peak d is upfield of peak g, so we can assign peak d to H3ax and peak g to H3eq (vicinal couplings to H2, peak i). Peak d has a quartet-like splitting pattern ( Q ), as expected for an axial proton (H3ax) with a geminal partner (H3eq) and two axial neighbors (H2 and H4ax). The only other vicinal coupling to H2 is H1, which has already been assigned (peak k). Starting again from the resolved peak d (H3ax) on the diagonal (~1.32 ppm), we can move up to a crosspeak with a wide footprint in F1 ( ppm) and a center in F1 that is slightly upfield of the peak b doublet. This can be clearly seen by comparing this crosspeak (F1 ~ 0.94, F2 ~ 1.32) to the crosspeak to its left (F1 ~ 0.95, F2 ~ 1.50). The center of this wide, short crosspeak (F2 ~ 1.50) is below the center of the roughly square peak d crosspeak (F2 ~ 1.32). The latter can be assigned to peak a in F1, which must be one of the protons on C4. In the top trace 1D spectrum, part of this peak can be seen to the right of the off-scale doublet (peak b). Looking at the top row of crosspeaks in the COSY expansion 2 we can see a short, wide crosspeak in the center (F1 = peak b, F2 ~ 1.50 ppm), two crosspeaks on either side of it that are slightly higher (F1 = peak a, F2 ~ 1.68 and 1.32 ppm), and a slightly lower crosspeak at the far left (F1 = peak c, F2 = 2.04 ppm). The distinction can also be seen clearly by moving down from the a/b/c peak on the diagonal: the two vertical streaks align with peak b, and one crosspeak is to the right of the streaks (F1 ~ 1.67) and one to the left (F1 ~ 2.04 ppm). 8-6

7 With one of the H4 peaks identified (peak a), we can look for its geminal partner. The reticence of peak e (H5) makes this difficult, but the only peak not yet assigned is peak f, the upfield peak of the f/g overlap. Peak a (H4eq or H4ax) has a crosspeak to both peak f and peak g (H3eq), so peak f must be the other proton on C4. A crosspeak to peak f alone can be found at the bottom of expansion 2, at F1 ~ 2.04, F2 ~ This crosspeak connects peak j (H6eq) to peak f (H4ax or H4eq). This long-range coupling ( 4 J) must be a W coupling, so peak f has to be H4eq. This is also consistent with its downfield position relative to peak a (H4ax). The width (F2 footprint) of the F2 = peak a crosspeak at F1 ~ 1.67, F2 ~ 0.93 is greater than the width (F2 footprint) of this W coupling crosspeak (F2 = peak f), also consistent with peak a assigned to H4ax (expected Q pattern) and peak f assigned to H4eq (expected D pattern). The very small chemical shift difference between peak f (H4eq) and peak g (H3eq) leads to very strong coupling via the equatorialequatorial J coupling (3-4 Hz). This distorts the coupling patterns of all their coupling partners, including H3ax (peak d), which should be a simple dq pattern. The peak labels, structural assignments and crosspeak assignments are shown below. 8-7

8 The assignment of peak m to H8t (trans to the cyclohexane ring) and peak l to H8c (cis to the ring) was based on the literature description of the 1D 1 H spectrum. The larger allylic coupling ( 4 Jhm = 1.5 Hz vs. 4 Jhl = 0.8 Hz) corresponds to the cis relationship between the C9 methyl group and the olefinic proton Hm, trans to the cyclohexane ring (compare 1-octene, Figure 5.15, limonene, Figure 5.21, and linalool, Figure 5.25). Solution Assignments are shown on the COSY spectrum and on the 1 H expansions below. The equatorial H1 has a long-range ( 4 J) coupling of 0.6 Hz to the axial H5 proton, nearly resolved in the H5 peak but giving only broadening in the H1 peak. The chair conformation is twisted due to the axial OH at C4 in both anomers, resulting in very different axial-equatorial couplings to H4 (1.1 / 3.5 Hz for the anomer, 1.3 / 3.4 Hz for the anomer). This twist may bring H5 out of a pure axial position and allow the W-type coupling to H1. 8-8

9 8-9

10 The anomer ratio is 30.6% to 69.4% (1:2.27). Solution D-Mannose: MHz 1 H spectrum (D2O): (t, J = 9.8 Hz, 1H), (dd, J = 12.0, 5.9 Hz, 1H), (dddd, J = 9.9, 6.0, 2.1, 0.5 Hz, 1H), (dd, J = 9.6, 3.4 Hz, 1H), (dd, J = 12.0, 2.2 Hz, 1H), (dd, J = 3.4, 1.8 Hz, 1H), (d, J = 1.8 Hz, 1H). -D-Mannose: MHz 1 H spectrum (D2O): (ddd, J = 9.8, 6.3, 2.3 Hz, 1H), (t, J = 9.7 Hz, 1H), (dd, J = 9.7, 3.3 Hz, 1H), (dd, J = 12.2, 6.3 Hz, 1H), (dd, J = 12.2, 2.4 Hz, 1H), (dd, J = 3.3, 1.1 Hz, 1H), (d, J = 1.1 Hz, 1H). Because the and forms are different molecules, close approaches of chemical shift (e.g., H4 and H3 ) do not lead to deviations from first-order splitting because there is no J coupling. The one close approach within the same anomeric form (H3 and H5 ) also has no J coupling. The barely-resolved doublet coupling (0.5 Hz) for H5 is a 4 J coupling to H1 (not resolved in the H1 peak). This can be described as a question-mark coupling (1,3-axial,equatorial) in a 8-10

11 cyclohexane chair, enhanced by the twisting of the chair. No analogous long-range coupling is seen in -mannose (H1 to H5 ) because in this case both protons are axial. This twisting is suggested by the smaller H1-H2 vicinal coupling in -mannose (1.1 Hz, axial-equatorial) than in -mannose (1.8 Hz, equatorial-equatorial). Generally, equatorial-equatorial couplings are smaller than axial-equatorial (Figure 6.33). In fact, because H2 is equatorial in mannose, the H1-H2 J value cannot be used to assign the anomeric stereochemistry by NMR. 8-11

12 Solution The trans CH=CH olefin can be assigned to peaks j and k based on their splitting patterns (d for peak j, dd for peak k) and chemical shifts (peak j in typical olefin range of 5-6 ppm, peak k shifted downfield due to its position to the ketone carbonyl). Peak h is correlated to peak k so it can be assigned to the allylic CH position in the cyclohexane ring. This completes one spin system. The remaining olefinic proton peak, peak i, is assigned by process of elimination to the remaining olefinic CH in the ring. Peak i is correlated to peak f, a complex 2H multiplet, so we can assign peak f to the allylic CH2 group in the ring. Peak i is also correlated to peak e, a singletlike methyl peak, so peak e can be assigned to the methyl group on the ring olefin (allylic coupling to peak i). Peak f is correlated to peaks c and d, which are correlated to each other (geminal pair), so peaks c and d can be assigned to the CH2 group next to the quaternary sp 3 carbon in the ring. The possibility that the geminal pairs are c/f and d/f, rather than c/d and f/f, can be ruled out because there is no correlation from peak i to either peak c or peak d. A weak correlation between peaks f and h is a bis-allylic ( 5 J) coupling. Although it doesn t show up on the other side of the diagonal, lowering the contour threshold reveals the expected weak crosspeak (not shown). Peak g has no correlations in the COSY spectrum, so it can be assigned to the methyl group next to the ketone. Peaks a and b are singlet methyl peaks which have correlations to each other (unresolved 4 J W couplings) through the quaternary carbon. These can be assigned to the geminal dimethyl group on the ring. 8-12

13 Solution See Solution 6.25c. The starting point is peak l, assigned by its chemical shift to the CH-O position (H2). The strong correlations from peak l to peaks d and k are vicinal relationships, so we can assign peaks d and k to the CH2 group at C3. The much simpler splitting pattern of peak d (dd) allows us to assign it to H3endo, since H3endo lacks the W coupling to H5exo and has a 90 o dihedral angle with H4, the bridgehead. The weak correlation from peak l to peak f is the W coupling from H2 (peak l) to H6exo, so we can assign peak f to H6exo. From peak k (H3exo) we can trace the couplings to peaks d (geminal) and g (vicinal), so peak g can be assigned 8-13

14 to the bridgehead H4. The weak correlation from peak k (H3exo) to peak h allows us to assign peak h to H5exo ( W coupling). From peak h (H5exo) we have correlations to peaks k (weak, H3exo), i, g (H4), f (H6exo) and e. Of these, only peaks e and i are unassigned and only the H6endo and H5endo positions remain unassigned in this spin system. To decide between the two possible assignments we first need to assign the singlet methyl groups. Peak j can be assigned to the acetate methyl because it has no COSY correlations and has a chemical shift (2.07 ppm) that is typical of methyl next to C=O. Peaks b and c are correlated to each other (box in upper right corner), so they can be assigned to the geminal dimethyl group, leaving peak a at the C1 (bridgehead) position. The long-range couplings to these three peaks (a, b and c) are interesting: peak i is correlated to peaks a and c, peak e to peak c only, peak d to peak b only, and peak g is correlated to all three. These weak correlation crosspeaks are observed on both sides of the diagonal. These are all either four-bond ( 4 J) W couplings or five-bond ( 5 J) couplings along a zigzag pathway. If we assign peak b to the methyl opposite the acetate group (CH3 trans ) and peak a to the methyl on the same side as the acetate (CH3 cis ), the correlation from peak d to peak b can be seen as an extended W (H3endo-C3-C4-C7-CH3 trans ). By analogy we can assign peak e to H5endo, so that its correlation to peak c is a similar W path: H5endo-C5-C4-C7-CH3 cis. The strongest correlation from peak g to the methyl singlets is to peak a (H4-C4-C7-C1-CH3), with weaker correlations to peaks b and c (4 bond W correlations with a non-planar path). The very weak correlations from peak g (H4) to peaks d (H3endo) and e (H5endo) are indications that these vicinal couplings are not exactly zero. Peak i can be assigned to H6endo, with a 4-bond W type correlation to the bridgehead methyl (peak a) and a 5-bond zigzag coupling to the C7 methyl on the opposite side (CH3 cis, peak c). Note that the 4-bond couplings are of the same magnitude or weaker than the 5-bond couplings because they are not aligned well in a planar W path. 8-14

15 Note that the height of the methyl peaks tells a story, since all have the same integral area (3H). Peak j is the tallest (no long-range couplings), and peaks b and c ( W coupled to each other) are the shortest (unresolved quartet coupling in addition to 4-bond coupling to H4 and 5-bond couplings to one or two of the three endo protons). Solution Using the COSY spectrum and starting with peak e (OH), the correlation to peak f means that we can assign peak f to H3. Correlation of peak f to peak j leads to assignment of peak j as H4. Peak j is correlated to peak l (H5), which is in turn correlated to peak i (H6b). Peak l also has a very weak correlation to peak h, which can be assigned to H6a. Peaks i and h are strongly correlated, since they share a large geminal coupling. Another spin system is comprised of peak g and peak k, with a geminal coupling connecting them. These can be assigned as the C1 CH2 group. Two more spin systems (long-range couplings) are peak a / peak d (geminal dimethyl 8-15

16 group) and peak b / peak c (the other geminal dimethyl group). Stereospecific assignments of the C1 and C6 CH2 groups, as well as the geminal dimethyl groups, requires NOE data. The geminal dimethyl groups can be assigned from the NOESY data. As expected from the 4 J ( W ) couplings in the COSY spectrum, peak a has an NOE correlation to peak d, and peak b has an NOE correlation to peak c. These are direct through-space interactions, in contrast to the through-bond interactions (J couplings) seen in the COSY spectrum. Peak a has NOE correlations to peaks i and j, placing this methyl group cis to these two protons on the 5-membered acetonide ring. Peak d has an NOE to peak f, since this methyl group (C12) is underneath the boat structure of the 6-membered ring (cis to C3 in the 5-membered acetonide ring). These correlations force us to assign peaks b and c in the other (C7-C9) acetonide. The crucial NOE here is from peak c to peak i, placing the peak c methyl group cis to O-C6 in the 5-membered acetonide ring and placing the peak i proton cis to O-C7 in the 6-membered ring. 8-16

17 With peaks i and c assigned, the C1 CH2 group can be assigned stereospecifically. Peak g has an NOE to peak c, so the peak g proton must be cis to the peak c methyl group in the 5-membered acetonide ring. Likewise peak k has an NOE to peak b, so the peak k proton is cis to the peak b methyl group, on the opposite side of the 5-membered acetonide ring. This assignment is confirmed by the NOE between peak f (H3) and peak k, with only a very weak NOE correlation from peak f to peak g. It can be seen in the structure diagrams that C3-Hf is parallel to C1-Hk, bringing Hf close to Hk. 8-17

18 8-18