J . Am. Chem. SOC.1986, 108, 6651-6661 like a simple phenol in water; however, since the pKa of a-T in SDS micelles is greater than 14,32,33 the concentration of the anion can not fully account for the pH dependence. Some other factor must be involved. One possible explanation is suggested by the observation that the pKa of a-T in micellar solutions varies with the nature of the micelle.33 It is possible that the micellar environment changes with pH, altering the extent of ionization of a-T. A pH-dependent change in the structure of the micelle also might change the rate of ozonation of the un-ionized form of a-T. At this time we suggest that the available experimental facts on the reaction of ozone with a-tocopherol are most consistent with a mechanism in which ozone oxidizes a-T to the a-T-oxy1 radical. Scheme I shows three possible mechanisms by which this oxidation could occur. Thermochemical considerations suggest that the direct hydrogen atom transfer (path a ) is too endothermic to occur readily. However, the same result can be obtained by either an electron transfer followed by a proton transfer (path k) or by a proton transfer followed by an electron transfer (path d-e). One-electron oxidations of phenols are ~ e l l - k n o w n and , ~ ~ the proton transfer from the resulting cation radical (path c) could be fast enough so that it is not observed.35 There is also ample precedent for charge transfer in ozonation reactions with electron-rich aromatic systems.36 In either case, additional stabi-
lization could be realized by solvation of the ozone radical anion and the proton. Clearly, the effect of pH suggests that path d-e predominates in aqueous media, although as discussed above, the pK, of a-T may require that path d-e not be the sole pathway involved; in other words, the actual mechanism may involve a mixture of the two pathways shown in Scheme I. Biological Significance. In biological membranes, the rate constant for ozonation of a-T would be at most comparable to that of a fatty acid. However, since unsaturated fatty acids are typically present in biological membranes at concentrations 100-IO00 times higher than a-T,37a-T would not compete for direct reaction with ozone. Additionally, since the ozonation products of methyl oleate do not react with a - T at temperatures of 37 OC and below, a-T is not consumed by secondary reactions of this type. Conclusions. When animals breath smoggy air, a-T is known to provide important p r ~ t e c t i o n . ~Since , ~ ozone would be expected to react virtually exclusively with PUFA in membrane lipids and not with the a-T directly, the protection that a-T provides against ozone must arise because a-T scavenges radicals produced from an ozone-PUFA r e a c t i ~ n , ~as- ~illustrated in eq 1 and 2. The
+ PUFA + a-T
03
ROO' (32) The pK, of a-T is about 12 in cationic micelles and about 13 in zwitterionic micelles (see ref 33). In an attempt to measure the pK, in SDS by the methods outlined in ref 33, we were only able to verify that the value was >13. (33) Drummond, C. J.; Greiser, F. Biochim. Biophys. Acta 1985, 836, 275-278. (34) (a) Grodkowski, J.; Neta, P. J . Phys. Chem. 1984, 88, 1205-1209. (b) Futamura, S.;Yamazaki, K.; Ohta, H.; Kamiya, Y. Bull. Chem. SOC.Jpn. 1982, 55, 3852-3855. (c) Huie, R. E.; Neta, P. Chem.-Biol.Interact. 1985, 53,233-238. (d) Svanholm, U.; Bechgaard, K.; Parker, V. D. J . Am. Chem. SOC.1974, 96, 2409-2413. (35) The pK, of phenoxy1 cation radicals is ca. -5 (see: Land, E. J.; Porter, G.; Strachan, E. Trans. Faraday SOC.1961, 57, 1885-1893) and, by analogy to H02' (pK, = 4.7; see: Bielski, B. H. J. Photochem. Photobiol. 1978, 28, 645-649), the ozone radical anion can serve as a proton acceptor in the absence of other nucleophiles. (36) (a) Pryor, W. A,; Ohto, N.; Church, D. F. J . Am. Chem. SOC.1983, 105, 3614-3622. (b) Desvergne, J. P.; Bouas-Laurent, H. J. Cafal.1977,51, 126-130. (c) Bailey, P. S.; Ward, J. W.; Carter, T. P., Jr.; Fischer, C. M.; Khashab, A. Y. J . Am. Chem. SOC.1974, 96, 6136-6140.
665 1
--
+
+
+
ROO'
nonradical products
(1)
(2)
direct, sacrificial reaction of ozone with a-T in biological membranes containing normal concentrations of unsaturated fatty acids does not occur.
Acknowledgment. This work was supported by grants from N I H (HL-16029) and N S F and a contract from the National Foundation for Cancer Research. We wish to thank Henkel Corp. (Minneapolis, M N ) for generous gifts of d-a-tocopherol. Registry No. a-T, 59-02-9; a-TQ, 7559-04-5; a-TAc, 58-95-7; a-Toxyl, 23531-69-3; 03,10028-15-6; 1,4-pentadiene, 591-93-5; oleic acid, 112-80-1; methyl oleate, 112-62-9; linoleic acid, 60-33-3; methyl linoleate, 112-63-0. (37) Underwood, B. A,; Denning, C. R.; Navab, M. Ann. N.Y. Acad. Sci. 1972, 203, 237-247.
170NMR Spectra of Cyclic Phosphites, Phosphates, and Thiophosphates Ernest L. Eliel,*la Subramanian Chandrasekaran,la Leslie E. Carpenter 1I,lband John G. Verkade*lb Contribution from the William Rand Kenan Laboratories, Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27514, and Department of Chemistry, Iowa State University, Ames, Iowa 5001 I . Received April I , 1985
Abstract: The I7O NMR spectra of a number of cyclic and bicyclic phosphites, phosphates, and thiophosphates are presented, and, in so far as possible, the I7O chemical shifts are interpreted in terms of conformational factors.
Following the pioneering work of Christ and Dieh12 a number of groups have studied the I7O spectra of various phosphorus derivatives including phosphites and phosphate^.^-]^ However, (1) (a) University of North Carolina. (b) Iowa State University. (2) Christ, H. A,; Diehl, P. Helu. Phys. Acta 1963, 36, 170. (3) Grossman, G.; Gruner, M.; Seifert, G.Z . Chem. 1976, 16, 362. (4) Gray, G . A.; Albright, T. A. J . Am. Chem. SOC.1977, 99, 3243. (5) McFarlane, H.C. E.;McFarlane, W. J . Chem. Soc., Chem. Commun., 1978, 531.
despite the importance of cyclic phosphates in biochemical processes and of cyclic thiophosphates as phosphate analogues useful (6) Tsai, M.-D.; Huang, S. L.; Kozlowski, J. F.; Chang, C. C. Biochemisfry, 1980, 19, 3531. Huang. S . L.; Tsai, M.-D. Ibid. 1982, 21, 951. (7) Coderre, J. A.; Mehdi, S.; Demou, P. C.; Weber, R.; Traficante, D. D.; Gerlt, J. A. J . Am. Chem. SOC.1981, 103, 1870. Gerlt, J. A,; Demou, P. C.; Mehdi, S. Nucleic Acids Res., Spec. Publ. 1981, 9, 1 1 ; J . Am. C,'rem. SOC.,1982, 104, 2848. Gerlt, J. A.; Reynolds, M. A,; Demou, P. C.; Kenyon, G. L. Ibid. 1983, 105, 6469.
0002-7863/86/l508-6651$01.50/0 0 1986 American Chemical Society
6652 J . Am. Chem. SOC..VoI. 108, No. 21, 1986
Eliel et al. Table 111. I7O N M R Spectral Data for the Thiophosphates 35-42"
Table I. I'O N M R Spectral Data for the Phosphites 1-9" compounds
OCHq
0-1
compounds
0-3
OCH,
0-3
0-1
35
36
37
38
39
40
41
42
"Chemical shift in ppm relative to external H 2 0 at 100 OC, in parentheses one bond P-0 coupling constant in Hz. bChemical shifts were estimated from overlapping signals for O(1) and O(3). cNot clearly resolved.
'Chemical shift in ppm relative to external H 2 0 at 100 OC;in parentheses, one-bond P-0 coupling constant in Hz. bChemical shift were estimated from overlapping signal for 0-1and 0-3. 'Not clearly resolved.
X
Table 11. I7O N M R Soectral Data for the PhosDhates 22-2Y compounds
-2"MH3
OCH3
0-P
0-1
0-3
22
OCH3 I
z;=_"o'px
3
4
24
25
23 7
8
28 -
29 -
24 11 -
25
12 -
26
27
x = 1 p
x = o x - s
15 2
14 32 43 -
28
29d
"Chemical shift in ppm relative to external H 2 0 at 100 OC; in parentheses, one-bond P-0 coupling constant in Hz. bNot clearly resolved. Chemical shifts and coupling constants were estimated from overlapping signal for 0-1 and 0-3. dConformation uncertain, see text, probably a mixture of conformers.
in stereochemical studies,"J2 in this category of compounds only "0-enriched cyclic 2'-deoxyadenosine-3',5'-monophosphate seems (8) Nieuwenhuizen, M. S.; Peters, J. A.; Sinnema, A,; Kieboom, A. P. G.; van Bekkum, H. J . Am. Chem. SOC.1985, 107, 12.
J . Am. Chem. Soc., Vol. 108, No. 21, 1986 6653
I7O N M R Spectra of Cyclic and Bicyclic Phosphites
Table V. Dipole Moments of Cyclic Thiophosphates 35-42
Table IV. Dipole Moments of Cyclic Phosphates 22-29
compound 22
35
5.63
OCH3
I
~ 23
fi
5.78
36
~
0
7 OCH3
I
p
~
(debye)
ref
4.77
a
5.50
b
4.20
b
s
zo7p"'s 24
4.93
a
37
Z Z p \ O C H 3
25
6.11 5.43
38
OCH,
5.52
a
26
4.69 4.73
39
w
3.98
a
27
5.57
40
OCH3
5.45
a
28
4.58
b
29
4.88
b
42
OCH3
5.31
a
I
I
b
o 0y dP
\
"Mosbo, J . A.; Verkade, J. G. J . Urg. Chem. 1977, 42, 1549. *This work.
"This work. *Bodkin, C. L.; Simpson, P. J . Chem. SOC.B 1971, 1136.
to have been examined by I7O NMR s p e c t r o ~ c o p y .We ~ ~ ~have now recorded the natural-abundanceI3 I7O spectra of the series of cyclic phosphites 1-21, phosphates 22-34, and thiophosphonates 35-43 (Tables 1-111, X, XI). The structural formulas for these systems are given in Chart I. In a number of cases the 31P170 coupling constants as well as the I7Ochemical shifts were recorded; however, because of the large bandwidth, the reproducibility of the coupling values between our laboratories and on repeat recordings within one laboratory was only fair, thus leading to a precision of no better than i10 Hz, and in some cases, notably for the C-0 signals of phosphates, the coupling was not clearly resolved. The accuracy and reproducibility of the chemical shifts, however, are of the order of f 2 ppm or better. Conformational Analysis. Before discussing the I7O data, it is necessary to analyze the conformations of the compounds studied, especially those with six-membered rings. The conformations of the cis-4,6-dimethyl derivatives 4, 5, 25, 26, 38, and 39 may be considered fixed as shown in Chart I. These compounds are the models in terms of which the conformations of the others may be discussed. Compounds 2,23, and 36 clearly have the same conformation as 4, 25, and 38, Le., the one shown in Scheme I with axial methoxyl (anomeric effect) and equatorial methyl. The 170chemical shifts for OCH3 and O(3) in the compounds of these two sets (Tables 1-111) agree we11.I4 In the case of the phosphates 23 and 25 (Table IV) and thiophosphates 36 and 38 (Table V), there is also fair agreement in the dipole moments which are characteristic of the methoxy 0rientati0n.l~ Unfortunately, the
I3C and ,'P spectra of the six-membered cyclic phosphates (Table VII), and thiophosphates (Table VIII) are not greatly affected by configuration or conformation, but in the case of the phosphites the 31P13C(5)coupling constant (Table VI) is characteristic, being of the order of 4-5 Hz for axial OCH3 compounds and 11-14 Hz for equatorial ones.16J7 By this criterion, compound 2 (like 4) clearly has an axial methoxyl. Proton-proton coupling constants of 23, 25, 26, 28, and 38 and 39 (Table IX) are in accord with the assigned chair conformations.18 The situation for the stereoisomers 3, 24, and 37 is not so clear-cut. Phosphite 3 has been claimed, on the basis of proton
(9) Vasilev, V. V.; Dmitriev, V. E.; Ionin, B. I.; Mets, V. N. J . Gen. Chem. U.S.S.R. 1981, 5 1 , 1836. (10) Gerothanassis, I. P.; Sheppard, N. J . Magn. Reson. 1982, 46, 423. ( 1 1) Eliel. E. L. 'Prostereoisomerism (Prochirality)"; Tor, Curr. Chem. 1982, 105, 1. (12) Floss, H. G . ;Tsai, M.-D.; Woodward, R. W. Top. Stereochem. 1984, 15, 253. (13) For earlier work, see: Eliel, E. L.; Liu, K.-T.; Chandrasekaran, S. Org. Magn. Reson. 1983, 21, 179. Manoharan, M.; Eliel, E. L. Magn. Reson. Chem. 1985, 23, 225. (14) Regarding the effect of the additional ring-methyl substituent, see: E M , E. L.; Pietrusiewicz, K. M.; Jewell, L. M. Tetrahedron Lett. 1979, 3649. (15) Mosbo, J. A.; Verkade, J. G.J . Org. Chem. 1977, 42, 1549.
(16) Infant'ev, E. E.; Borisenko, A. A.; Sergeev, N. M. Proc. Acad. Sci. USSR, Phys. Chem. Sect. 1973, 208, 100. (17) (a) Haemers, M.; Ottinger, R.; Zimmermann, D.; Reisse, J. Tetrahedron 1973, 29, 3539. (b) E M , E. L.; Pietrusiewicz, K. M. '"C NMR of Nonaromatic Heterocyclic Compounds"; Top C-13 NMR Specfrosc. 1979, 3, 171. (18) The proton-proton coupling constants in Table IX were recorded at room temperature. The referees have questioned whether the inference of one greatly predominant chair conformation is still justified at 100 "C. In the light of their comments we have also recorded the proton spectra of compounds 22-24,26, 29,36,37, and 40-42 at 25 and 100 OC in toluene-ds (there is an appreciable ASIS shift relative to CDC13at 25 "C). The coupling constants for 23, 26,36,37,40, and 41 change very little with temperature, suggesting that the conformations at 100 and 25 "C are very similar (chair for 23, 26, 36; chair or rigid boat for 40 and 41; very predominantly diequatorial chair for 37). The spectrum for 24 was too tightly coupled for a meaningful first-order analysis, but again there was little change in the basewidth of the peaks with temperature. Compound 22 showed a marked increase in basewidth for H(5), and a decrease for H(5),, suggesting an increase in proportion of either an alternative chair (equatorial OCH,) or twist form. This is somewhat at odds with the evidence from "0 spectra (Table 11) which suggests very predominantly axial OCH3 even at 100 OC. Compounds 29 and 42 show increased conformational averaging at 100 OC as compared to room temperature, to the extent that the spectrum of 29 at 100 OC becomes difficult to analyze. This problem is less serious for 42 in which, however, J H A H drops to 8.4 at 100 "C. Nonetheless, the axial OMe conformer appears to be Avored in both compounds even at 100 "C, as indicated in the discussion. Comparison of spectra at 25 and 100 "C bears out the above conclusions. In most instances the shifts vary by 0.0-0.6 ppm. Exceptions are 29 [C(4) and C(5) vary by 0.7 ppm], 41 [C(5) varies by 0.7 ppm], and 42 [C(4) varies by 1.1 ppm, C(5) by 0.7 ppm]. However, because of the insensitivity of the ')C spectra to conformation (see text), these results are less significant than those reported above for the proton spectra.
6654 J. Am. Chem. Soc.. Vol. 108, No. 21, 1986
Eliel et al.
Table VI. I3C and "P N M R Parameters for Cyclic Phosphites 1-8 at 25 "C" compound
solvent
c-4
c-5
C-6
OCH,
none
59.5 (1.6)
29.4 (5.5)
59.5 (1.6)
OCH3
none
66.0
36.5
60.0
(2.0)
(4.7)
(2.5)
CDZCI,
69.8 (3.6) 69.6
34.0 (10.8) 33.6 ( 12.0)
CDCl3
65.7
69.7
I
I
none Z o f \ O C H 3
31P
ref
49.8 ( I 7.8)
131.0
b, c. d
23.4
49.8 ( 1 8.0)
129.8 125.9
b, c, e
(3.2)
59.0 (1.8) 58.8
23.5 (1.6) 23.1
49.2
123.5
b, c, e
( 1 4.7)
42.7 (4.2)
65.7
22.5 (3.2)
40.8 (1 3.5) 41.4 ( 1 3.8)
69.7
22.5 (3.2)
49.4
127.2 129
c, d
23.3 (1.6) 23.7
48.2
131.5 133
c,d
70.2
23.3 (1.6) 23.7
46.8 (6.0)
62.3 (2.0)
28.5 eq 33.1 ax
23.1 (3.6)
49.6 (20.0)
129.9 128.6
Ag
CD2C12
44.4 (1 6.0)
67.3 (6.0)
28.6 eq 32.3 ax
24.1
49.1 ( I 8.0)
131.1 129.7
g
CD2CI2
39.9
61.6
23.0
23.1
49.6
131.9
75.7 (6.0)
OCH3 I
&+OCH3
8
C-2B
126.5
70.2
7
C-6a
49.3 (15.0)
S Z p \ O C H 3
6
C-4a
(7.0)
48.8 (10.0)
f
( 1 9.4)
"Values in parentheses are 'lP-laC coupling constants in Hz. bNifant'ev, E. E.; Borisenko, A. A.; Sergeev, M. M. Proc. Acad. Sci. USSR Phys. Chem. Sect. 1973, 208, 100. c13Cand '[P: Haemers, M.; Ottinger, R.; Zimmerman, D.; Reisse, J. Tetrahedron 1973, 29, 3539. d31P: White, D. W.; Bertrand, R. D.; McEwen, G. K.; Verkade, J. G. J . A m . Chem. S o t . 1970, 92, 7125. Mikolajczyk, M.; Luczak, J., Tetrahedron 1972, 28, 541 1. /I3C and "P: this work. p a l p : Nifant'ev, E. E.; Sorokina, S . F.; Borisenko, A. A,; Zavalishina, A . 1.; Komolova, G . V., Z h . Obshch, Khim. 1978, 48, 2378; Engl. transl., p 2158.
coupling constant, to be 16% in the diequatorial conformation, 44% in the diaxial, and 40% in the boat form.Ig Neither the 170 spectrum (Table I) nor the 31P-13C(5)coupling constants (Table VI) are in accord with so low a percentage in the diequatorial chair conformer. If one assumes, reasonably, that the boat form would resemble, in I7O chemical shift and 31P-13Ccoupling constant, the chair conformer which possesses an axial OCH3, the I7Oshift suggests about 70%and the coupling constant indicates ca.70-8W0 diequatorial chair. An estimate of approximately 70%diequatorial chair and the rest diaxial chair or boat for phosphite 3 would seem reasonable and in qualitative accord with earlier work.20 Phosphate 24 has been alleged,21a also on grounds of proton coupling, to be 60% in the diequatorial and 20%each in the diaxial and boat forms (where the terms equatorial and axial refer to the methoxyl group on phosphorus). However, the I7Oshifts for both the methoxyl and phosphoryl oxygen in 24 are very close to those in 26 and from the earlier measured dipole moments1s of 23, 24, and 26, over 80% of 24 would appear to be in the "diequatorial" conformation. Thus the estimate of only 60% of that conformation2Ia seems somewhat low. Nonetheless, it appears that neither 3 nor 2422nor the thiophosphate 37 is conformationally homogeneous; in the case of the latter compound, dipole moments (Table V) suggest somewhat under 90% of the diequatorial Me-Me0 conformation in accord with an earlier report.20 In the case of the ring-unsubstituted compounds, the phosphite 1 is believed, on the basis of its 13C(5)-31Pcoupling constant (Table VI), to exist largely or exclusively in the MeO-axial conformation,16,23and this is borne out by comparison of the I7Oshifts of (19) Borisenko, A. A.; Sorokina, C. F.; Zavalishina, A. I.; Nifant'ev, E. E. Proc. Acad. Sci. USSR, Chem. Sect. 1978. 241, 359. (20) Bodkin, C.; Simpson, P. J . Chem. SOC.,Chem. Commun. 1969. 829; J . Chem. SOC.B 1971, 1136. (21) (a) Mosbo, J. Org. Magn. Reson. 1978, 11, 281. (b) Bock, P. L.; Mosbo, J. A,; Redmon, J. L. Ibid. 1983, 21, 491. (22) See also: Majoral, J.-P.; Navech, J. Bull. SOC.Chim. Fr. 1971, 95, concerning the corresponding phenoxy compounds.
the methoxy group and the 0 ( 1 ) ring oxygen with the corresponding shifts in 2 and by comparison of the I7O shift of the methoxy group in 4 (Table I). In the phosphate 22 the conformer with axial M e 0 has been found to be the predominating or exclusive 0ne,15922,24 and again this is borne out by comparison of the I7O shifts (Table 11) of MeO, O=P, and 0 ( 1 ) with the corresponding shifts in 23 and by comparison of the I7O shifts of the M e 0 and O=P groups in 25. Less information is available in the literatureZSon the thiophosphate 35, and the I7Oevidence for axial M e 0 (Table 111) is not quite conclusive here. While the shift data for OMe agree with those of 36 and 38, O( I ) shifts of 35 and 36 are not in accord. The dipole moment of 35 (Table V) suggests that it exists as a conformational mixture. The situation with the trimethyl compounds 6, 7, 27, 28, 40, and 41 has not been extensively explored in the literature. In the case of the phosphites (6, 7), I3C NMR data (Table VI) point to predominant chair conformations with axial and equatorial alkoxy1 groups, respectively. [The changes in chemical shift relative to 4 and 5 are reasonable for introduction of an additional axial methyl group, and the 31P-13C(5)coupling constants differ in the expected way between the stereoisomers, though their absolute values are somewhat large in both cases.] The O( 1) shift (Table I) in 6 agrees well with that in 4 but that in 7 is disturbingly far upfield (5 ppm) from that of 5. The contribution of boat or twist forms cannot be excluded with either isomer. The low-field shift of M e 0 in 6 could be explained by a boat form, but it is equally consistent with a &compression effect in the chair (see below). The low-field I7O shift of OMe in 7 is hard to explain on any grounds (see later discussion). In the case of the phenoxy (23) See also: Maryanoff, B. E.; Hutchins, R. 0.;Maryanoff, C. A. Top. Stereochem. 1979 11, 187. (24) Regarding the corresponding phenoxy compound, see ref 22; the compound is in the chair conformation with axial C6HS0in the solid state: Geise, H. J. R e d . Trau. Chim. Pays-Bas 1967, 86, 362. ( 2 5 ) See ref 23, p 223.
I7O N M R Spectra of Cyclic and Bicyclic Phosphites
J. Am. Chem. Soc., Yol. 108, No. 21, 1986 6655
Table VII. I3C and ” P NMR Parameters for Cyclic Phosphates 22-29 at 25 OC’ compound 22
solvent CDCli toluene-d8
23
CDCI, toluene-d8
24
CDCI, toluene-d8
25
CDCI,
26
CD2CI2 toluene-d8
27
CD2C12
c-4
c-5
C-6
69.2 (5.7) 68.8 (7.3) 77.5 (5.7) 76.9 (6.9) 76.4 (5.7) 76.0 (5.6) 76.1 (7.6)
26.1 (7.6) 26.2 (7.5) 33.4 (5.7) 33.2 (5.6) 32.6 (5.7) 32.7 (5.8) 40.5 (5.7)
69.2 (5.7) 68.8 (7.3) 68.3 (5.7) 68.0 (7.0) 66.7 (5.7) 66.6 (5.7) 76.1 (7.6)
75.1 (7.0) 74.4 (4.8) 83.4
40.8 (5.8) 40.7 (5.4) 44.6 (6.0)
75.1 (7.0) 74.4 (4.8) 72.9 (6.0)
82.6 (6.0)
44.6
(8.0)
73.1 (6.0)
72.9 (7.6) 73.7 (6.4) 72.1 (7.4)
37.5 (7.6) 37.9 (4.1) 37.5 (7.6)
74.7 (7.6) 75.7 (6.5) 73.7 (7.3)
(8.0) 28
29
CD2CI2
CDCI3 acetone-d6 toluene-d8
c-4a
-
C-6a
C-2p
“P
-
53.6 (5.7) 53.0
-6.7
ref
(5.7)
22.3 (9.5) 22.1 (9.0) 21.7 (5.7) 21.6 (6.8) 22.1 (9.5) 22.2 (8.0) 22.1 (9.3) 31.8 eq (1 0.0) 25.8 ax 30.9 eq (6.0) 27.3 ax 20.5 20.7 20.5
-
53.6 (5.7) 52.9 (5.6)
-6.4
-
54.6 (5.8) 54.2 (7.0) 53.4 (3.8)
-4.6
22.2 (8.0) 22.1 (9.3) 22.3 (9.8)
54.8 (7.6) 54.2 (5.8) 53.8 (6.0)
-4.9
22.5 (8.0)
54.5 (6.0)
-6.1
21.9 (7.6) 22.0 ( 1 2.3) 21.8 (7.4)
53.8 (5.7) 53.9 (5.7) 53.3 (5.8)
-6.1
22.1
-7.1
-7.6
“Values in parentheses are 31P-13Ccoupling constants in Hz. b13Cand ,IP: This work. c3’P: Mosbo, J. A.; Verkade, J. G. J . Org. Chem. 1977, 42, 1549. d31P: Mosbo, J. A,; Verkade, J. G. J. A m . Chem. SOC.1972, 94, 8224.
analogues of the phosphates 27 and 28 (Table 11), it has been suggested that the analogue of 27 exists as a chair, but that the analogue of 28 is possibly in a twist form.26 However, the dipole moments of 27 and 28 (Table IV) are in the normal range for chair conformers (if perhaps slightly on the low side), their I3C spectra (Table VII) show no obvious anomalies, and the proton spectra (Table IX) show a normal “backbone” thus excluding twist (but not classical boat) conformations. The I7O spectra are not directly interpretable in terms of conformation and do not settle the question of twist or boat contributions. The proton-proton coupling constants in 27 and 28 as well as 40 and 41 exclude twist forms and suggest chair conformations as shown in Chart I for these compounds, though the high dipole moment of 41 (Table V) may point to a contribution from a rigid boat form with equatorial S and axial OCH3. No information appears to be available in the literature regarding the trans-4,6-dimethyl compounds 8, 29 and 42. In the phosphite 8, the inequality of the C(4) and C(6) shifts (Table VI) and of the O(1) and O(3) signals (Table I) militates against a twist form and also against a near 5050 conformer mixture. The 31P13C(5)coupling value of 7.0 Hz does suggest a mixture of conformers, but with the one having an axial M e 0 predominating. The proton-proton coupling constants (Table IX) support this hypothesis, as does the fact that the shift of the I7OMe signal of 8 is somewhat downfield of that in 6 but appreciably upfield of signals are nearly that in 7. The finding that the two methyl equal and occur near 23 ppm also speaks against the presence of a major amount of the conformer with equatorial OMe in which the axial MeC(6) would have to appear in the 17-19-ppm region. C(5) is somewhat downfield from the position it occupies in rrans-4,6-dimethyl-substituted1,3-dioxanes (Le., 36.5-37.5 ~ p m ) . ~ (26) Majoral, J.-P.; Navech, J. C. R. Seances Acad. Sci. 1969, 268, 21 17; Bull. SOC.Chim. Fr. 1971, 1331.
This is typical of axial but not of equatorial OMe phosphites as is shown by comparing data in Table VI with C(5) in 1,3-dioxane (26.6 ppm) and its 4-methyl (33.7), cis-4,6-dimethyl (41.1), and 4,4,6-trimethyl (44.2 ppm) derivative^.^^ The situation is less clear for the phosphate 29. Its dipole moment (Table IV) would seem to point either to a predominantly equatorial methoxyl or to a twist form. On the other hand, a proton N M R study2aof the corresponding phenoxy compound suggests it to be a mixture of chair conformations in which the one with axial OPh predominates to the extent of 7 0 4 0 % and the coupling constants in Table IX support an analogous situation in the case of the OMe compound 29. The hypothesis of a conformer mixture is supported by the close similarity in chemical shifts of C(4) and C(6)29(Table VII) and of 0 ( 1 ) and O(3) (Table II), the upfield shift of the two methyl groups (Table VII) relative to those in the phosphite 8, the intermediacy of the I7OMe shift between those of 27 and 28 (Table II), and the effect of temperature on the proton spectrum.ls The 170=P shift of 29 is closer to that of 27 (axial OMe), but the corresponding coupling constant is closer to that of 28. The dipole moment (Table V) of the thiophosphate 42 suggests that it exists largely in the OMe-axial conformation, and this is supported by the proton-proton coupling pattern (Table IX), by the effect of temperature on the proton spectrum,I8 and by the I7OMe shift relative to the corresponding data for 40 and 41 (Table 111). The equivalency of the 0 ( 1 ) and O(3) signals is probably not significant since the (analogous) O(1) shifts in 40 and 41 also do not differ much from each other. The I3Cspectrum of 42 (Table VIII) is compatible with a predominantly axial OMe, but it cannot be claimed as strong evidence one way or the other. The I7O ~ (27) Pihlaja, K.; Nurmi, T. Isr. J. Chem. 1980, 20, 160. (28) Hall, L. D.; Malcolm, R. B. Can. J . Chem. 1972, 50, 2102. (29) This evidence must be viewed with caution since C(4) and C(6) are also nearly equal in r-2,cis-4,~rans-6-trimethyl-1,3-dioxane, even though this compound is conformationally homogeneous.*’
Eliel et al.
6656 J . Am. Chem. SOC..Vol. 108, No. 21, 1986 Table VIII. I3C and ,IP NMR Parameters for Cyclic Thiophosphates 35-42 at 25 OC compound
solvent
c-5
c-4
C-6
-
C-6cu
C-2p
"P
ref
-
54.3 (5.0)
64.4
b
53.9 (7.0) 53.3 (5.1)
64.1
b, c
66.1
b, c
35
CDCI,
67.9 (8.0)
26.3 (7.0)
67.9 (8.0)
36
CDCI,
76.5 (8.0) 76.3 (7.7)
33.2 (7.0) 33.3 (6.0)
67.5 (8.0) 67.6 (9.4)
22.4 (9.0) 22.3 (9.5)
-
75.7 (7.0) 75.5 (4.0) 75.6 (8.0)
33.5 (5.0) 33.6 (5.3) 40.4 (5.5)
66.4 (6.0) 66.4 (5.2) 75.6 (8.0)
21.9 (9.0) 21.9 (9.2) 22.2 (10.0)
22.2 (10.0)
54.9 (7.0) 54.6 (5.7) 53.7 (5.5)
22.1 (11.0)
22.1 (11.0)
54.9 (6.0)
toluene-d,
CDCI,
37
toluene-d, 38
CDCI3
39
CDCI3
74.7 (4.0)
41.2 (5.0)
74.1 (4.0)
40
CDCI,
83.9 (9.9)
44.3 (5.7)
72.2 (7.8)
toluene-d,
83.4 (10.9)
44.1 (5.7)
72.0 (7.8)
CDCI,
83.6 (7.9)
43.8 (9.5)
72.8 (6.6)
toluene-d,
82.9
43.8 (7.8)
72.2 (5.6)
41
(8.0) 42
72.8 75.5 37.9 (8.0) (8.0) (8.0) 72.1 toluene-d8 74.2 37.7 (7.6) (9.3) (7.6) "Values in parentheses are 31P-'3C coupling constants in Hz. b13Cand 31P: this 541 1. Table
C-4a
CDCI3
-
-
22.4 31.9 eq (9.3) (5.3) 26.3 ax 31.9 eq 22.3 (9.4) (9.5) 26.2 ax 31.1 eq 22.3 (9.1) (3.6) 27.3 ax 22.4 31.2 eq (4.1) (7.5) 27.1 ax (2.8) 22.2 21.1 (8.0) 22.0 21.0 (7.5) (3.7) work. c31P: Mikolajczek, M.;
54.1
b
b
62.5
b
62.6
b
53.7 (3.8) 54.4 54.1 (5.0)
b 54.5 63.9 (6.0) 53.9 (3.7) Lucak, J. Tetrahedron 1972, 28,
IX. Backbone Coupling Constants in Hz (First-Order Analysis, JnpH, Not Included)
HB
compd
R
H H H H CH3 CH3 CHI CH, H H H CH3 CH3 CHI CH3 H "This compound has no methyl 1 1.5, J H E H C 5.0, J H ~-1H1.5 ~ Hz. 8 22" 23 24 25 26 27 28 29 36 37 38 39 40 41 42
R' CHI H H H H H CH3 CHI CH3 H H H H CH3 CH3 CH, substituent.
X
Y
OMe OMe OMe =O OMe =O OMe =O OMe OMe
3JH~H~
9.4 =O =O 11.4 OMe 12 =O 11.3 OMe 11.3 11.5 =O OMe 11.7 =O 9.0 =S 11.5 =S OMe 10.7 OMe =S 10.9 =S OMe 11.2 =S 11.5 OMe OMe 11.7 =S OMe =S 9.2 bJHEHC = 2.6, J H E ~ = B 9.3 Hz. 'Spectrum
spectrum of the 4,4,6,6-tetramethyl phosphite 9 is compatible with an all-chair form with axial methoxyl. The remaining compounds are either conformationally locked (bicyclic systems) or highly mobile (five-membered rings). 170-31P Coupling Constants. Unfortunately, because of the large bandwidth of the I7O signals, the reproducibility of the
lJHgHc -14.0 -14.8 -14.8 C -17.3 2.4 -14.3 2.4 -14.3 2.3 -14.3 2.6 -14.6 4.1 -14.6 2.2 -15.0 2.8 -14.6 2.7 -14.5 2.4 -14.4 2.3 -14.3 2.6 -14.5 3.8 -14.6 not fully analyzed; J
3JH~H~
'JH~JHc
3.2 2.4
H ~ H=~
3JH~Hg
3.2 2.6b 2.4 c
5.0 5.96 6.2 c
3.2 1.9d 2.9
5.2 1.9d 5.1
3.8 11.5, J
5.2 HZ.
H ~ H=~ 4.2
d J ~ E ~ E
coupling data in Tables 1-111 (which in some instances contain data from two laboratories) is quite low and the accuracy of these constants is probably no greater than f10 Hz (cf. ref 2, 4, and 5) overall. These data are somewhat less good (&I5 Hz) for the ring oxygens whose signals tend to be particularly broad, and somewhat better (i5 Hz) for the rather narrow phosphoryl ox-
I7O N M R Spectra of Cyclic and Bicyclic Phosphites
J . Am. Chem. Soc., Vol. 108, No. 21, 1986 6651
Table X. I7O Resonances of Five-Membered Cyclic Phosphites, Phosphates, and Thiophosphate 43’ compd
14
15
16
17
18
19
20
21
32b
33‘
34d
43
104.6 77 125 100 133.4 151.0 156 28.7 60 34 61.8 67.4 e e 196 159 111 e 176 155 78 e e 127 JP-OR 127 125 78.4 79.6 79.3 81 78.7 78.6 46.1 48 96 71.5 6P-Gring 144 e e 154 152 122 e 88 e e 127 JP-O-nng 156 “Shifts in ppm, coupling constants in Hz. bP=O, 77.9 (166 Hz). ‘P=O, 80.2 (163 Hz). “P=O, 88.8 (159 Hz). eNot determined. b 0 R
Table XI. 170Resonances in Bicyclic Phosphites and Phosphatesn compd 10 11 6 71.4 91.6; 116.6 J 159 152; 133 “6 in ppm, J in Hz. bNot determined. (P=O resonance.
12
13
30
31
80; 84; 104.2 189; 170; 129
82.7 152
51; 68.4( b; 150
76; 93.OC b; 150
ygens. For the phosphites (Table I) the 31P-170coupling constants fall into the 150-180-Hz range and are thus similar to that for P(OMe)3 (1 542 or 153 Hz5). In most of the phosphates (Table 11) 3 1 P 1 7coupling 0 constants for single-bonded P-0 were not resolved.30 The P=O coupling constants, in contrast, are well resolved; they fall in a narrow range (156-1 64 Hz except for 27) which is in better agreement with one reported2 (MeO),P=O coupling constant of 165 Hz than with another report4 of 145 Hz. The reason for the low P=O coupling constant for 27 is not obvious. The range for the thiophosphates (Table 11) is 92-1 27 H z for all P-0 couplings. I7O Chemical Shifts. Examination of the phosphite 170shifts in Table I, especially those for 4 vs. 5 and 2 vs. 3, indicates substantial and easily detectable differences in the I7O signal positions of axial and equatorial methoxyl groups. The axial I7O nucleus resonates upfield of the equatorial, in accord with the earlier observation in conformationally locked cyclohexanols and their ethers.13 This is of particular interest, since the 13Cand 31P spectra of the isomers 4 and 5 (Table VI) are quite similar except for a small upfield shift (4 ppm) of C(4,6) in the axial isomer and the already-mentioned enhancement of the 31P13C( 5 ) coupling in the equatorial one. The differences between stereoisomers for the ring oxygens [0(1,3)] is quite small (
