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Phosphate basicity and nucleophilicity loss upon constraint: The role of the alkoxy oxygens
165
BIOINORGANZC CHEMISTRY 3, 165-182(1974)
Phosphate
Basicity
Constraint:
The
and Role
Nucleophilicity of the
Alkoxy
Loss
Upon
Oxygerns
J. G. VEXKADE GaYmanHall Deparhent of ChemaNry,Iowa Stak UntierszXy,Ames, Iowa 6ooIO
ABSTRACT Structural evidence is cited which suggests that the POC angle is more flexible than the OPO angle when phosphateesteralkoxygroupsare con-
strainedinto rings. In hybridizationterms, the tendencyfor the POC angieto decrease from ca. 120” in acyclic systems to probably less than li5” in O=P(O)(OCH&CH is consistentwith the notion that an sp” alkoxy oxygen is less capable of pi bonding to phosphorusand consequently
the negative charge on the phosphorus and hence also on the phosphoryl oxygen is dccresed. The &Yerence in orbital co&gurations in acyclic phosphates and in monocyclic and bicyclic analogues has an effect which is seen to re-enforce the hybridization argument. These simple considerations are shown to account for the bulk of the evidence demonstrating that phosphate ester nucleophilicity and bssicity decreases on constraiut of these systems. The “hinge effect” described above for oxygen in phosphates also appears to play a role in varying the basicities of phosphites and also possibly in the acidity changes in certain borate derivates on constraint. Nitrogen apparently also displays a %inge effect” in several amino phospbiue systems. KEY
PHRASES
Phosphate Orbital Symmetries; Cyclic Phosphates and Phosphites; POC Angle Variations in Phosphates and Phosphites; Alkoxy Oxygen “Hinge Effect”; Toxicity.
INTRODUCTION Much evidence has accrued over the past decade regarding the biological of constrained phosphorus heterocycles, such as the cellular
importance
@ AmericanEZsevierPublishing Company, Inc., 1974
_ 180
J. G. VEFtKADE
evidence, results in negative charge concentration on the alkoxy oxygens at the expense of phosphoryl oxygen basicity and phosphorus nucleophilicity.This charge rearrangementbecomes reasonable if the sp* alkoxy oxygens in acyclic phosphates gain p character on constraint, thereby losing pi donating ability to phosphorus. Pi bonding loss is ah indicated by less phosphorusd orbital involvement on symmetry grounds in mono- and bicyclic phosphates compared to acyclic anslogue~. Simikw reasoning can be applied to phosphites. It must be recognized, however, that even though most phosphitesincluding P(OCH2)3C31e are probably strainless, the species of importance in electrophilicattack is four-coordinate, and the phosphorus polarizabiity by the electrophileis dependent on the ease xith which OPO bond angle opening can be achieved, and this property in turn is a function of the degree of constraint. structural
The author thanks the ~Vaticw& Cancer Institule (NIH WSSW& gr~7bt 15969-01) and th.e .Natiunnl Science Foundtiitm (Grant GPSSS 76x) for genewus support of this W&L REFERENCES
AND NOTES
1. F. H. Westheimer, Acwunfs C&R. Res. 1,70 (1968). 2. G. Aksnes and K. Bergesen, Ada Churn.Stand. 20,2508 (1966). 3. F. IF_ Westheimer, in Chimie Organiquedu Phosphore, Centre National de la RechercheScientifique, Paris (1910), p. 307. 4. (a) G. Akmes, private communication, (b) D. W. White and J. G. Verkade, unpublished_ 3. S. C. Goodman and J. G. Verkade, Inmg_ Chem. 5,498 (1966). 6. L. J. Vande Griend, D. W. White, and J. G. Verkade, Phosphorus3,s (1973). 7. (a) A_ L. Mixon and W. R. Gilkerson, J. Phys. Chem. 75, 3309 (1971); (b) J. H. Finley, D. Z Denney, and D. B. Denney, J. Amer. Chem. Sot. 91,5026 (1967). 8. D_ A. Usher, E. A. Dennis, and F. H. Westheimer, J. Amer. Chem. Sot. 87,232O (1965). 9. G_ M. Blackbum, J. S. Cohen, and Lord Todd, TetrahedronL&!ers 2873 (1964). 10. G. I&f.Blackburn, 3. S. Cohen, aud 1. Weatherall, Tefrahedron27,2903 (1971). 11. R L_ Collin, J. Amer- Chem. Sot. 88,3281(1966). 12 D_ Boyd, .J_Amer. Chem. Sot. 91,120O (1969). 13. J. C_ Clardy, D_ Truesdale, and J. G. Verkade, unpublishedrewlts. 14. G. Akmes and R Eriksen, AC&Z Chem. Sand. 20,2463 (1966). 15. (a) R F. Hudson and C. Brown, Accoznk Chem. l&s. 5,204 (1972) and references therein; (b) R. Greenhalgh and R F. Hudson, Phtwplumrs2,l (1972). 16. D. A_ Denney md F. A_ Wagner, Phosphm-us3,27 (1973). 17. D. W. White and J. G. Verkade, Phosphorus3,9 (1973). 18. C. k Streuli, AnuZ. Chem 32,985 (1960)_ 19. E_ M_ Thorsteimon and F. Basolo, J. Amer. Chem. SOC.88,3929 (1966). 20. L. J. Vande Griend and J. G. Verkade, Phm-phams3,13 (1973).
PHOSPHATE
BASICITY
AND
NUCLEOPHILICITY
181
21. R. D. Bertrand, J. G. Verkade, D. W. White, D. Gagmire, J. B. Robert, and J. Verrier, J. &fag_Res. 3,494 (1970). 22. (a) W. Irving, Hooker Chemical Corporation, private communication. @) N. 1. Sax, in Dangerous Properties of Indu&iaZ MabzhZs, Reinhold, New York (1966). 23. (8) R. D. O’Brien, C. Y. Chiu, and J. G. Verkade, unpublished results. @) E. M. E!elIetand J. E. Cssida, private communication. 24. R. L. Keiter and J. G. Verkade, Inerg_ Ch. 9,404 (1970). 25. L. G. Vande Griend and J. G. Verkade, to be published. 26. J. G. Verkade, in Chimfe Organiquedu Phosphore, Centre National de la Recherche ScIentifique, Paris (1970), p. 5. 27. J. G. Verkade, Coord. Chem. Rev. 9,l (1972) and references therein. 28. M. E. Brennan, J_ Chem. Sot_ D, 956 (197O)o). 29. It should not be inferred here that spa lone pair orbit& are necessariiy devoid of pi bonding capability. It has heen shown theoretically (M. J. S. Dewar and P. Rono, J_ A-_ Chem. L&C_91,2!259 (1969)) that pyramidal nitrogens are capable of eonjugating with adjacent unsaturated systems and that the resonance interactions are about four-fifths as effective as planar nitrogen_ If such a pomibiity exists in the case of oxygen in phosphorus esters, the argument would not be altered, however, since the trend would be the same. 30. R. B. Wetzel and G. L. Kenyon, J. Amer. Chem. Sot_ 94,9231 (1972). 31. D. E. C. Corbridge, in Topics in Phosphorus ChemzMy, (M. Grayson and E. J. Griffith, Eds.), Wiley Interscience, New York (1966), p_ 57. 32. D- W. J. Cruikshank, J. Chem. Sot., 5436 (1961). 33. M. G. Newton, J. R. Cox, and J. A. Bertrand, J. A-_ Chem. SOC.88,1503 (1966) and referencestherein_ 34. W. 0. Davies and E. Stanley, Ada Cryslauogr. 15,1OQ2 (1962). 35. (a) D. Swauk, C. N. Caughlan, F_ Ramirez, 0. P. Madan, and C. P. Smith, J. Ave. Chem. Sot. 89, 6603 (1967); (b) T. A. Seits and W. N. Lipscomb, Zbid 87, 2488 (lQ6+ 36. H. J. Geise, Rec. Tran. Chim. 86,362 (1967). 37. D. M. Nimrod, D. R. Fitzwater, and J. G. Verlcade, Znosg. Chim. Acta2,149 (1966). 38. J. C. Clardy, D. C. Dow, and J. G. Verkade, to he published. 39. P. Anderson and K. E. Hjortaas, Aah Chem. Sccmd.14,829 (1960). 40. In the five-membered ring systems and the bicyciic systems the PCC angle is less than 12OO”. Thus, although this p orbital attains some s character in the process, pi bonding is not excluded even though it is diminished (see [26]). 41. E. E. Nifant’ev, A. A. Borisenko, I. S. Nasonovskii, and E. I. Matrosov, DokZ. Akd Nauk USSR I%, 23 (1971) (Engl.). 42. J. A. Mosbo and J. G. Verkade, J. Amer. Chem. Sot. 95,204 (1973). 43. J. A. Mosbo and J. G. Verkade, J. Amer. Chem. Sot., in press. 44. J. Rodgers, D. W. White, and J. G. Verkade, J. Chem. Sot. A, 77 (1971) 45. J. A. Mosbo, J. C. Chudy, and J. G. Verkade, J.C.S. Chem. Cumm., 1163, (1972). 46. L. J. Vande Griend and J. G. Verkade, Znorg. A&Z. Chem. Letfers,9,1137 (1973). 47. D. W. White and J. G. Verkade, Phosphorus 3,15 (1973). 46. J. R. Durig and J. M. Caspar, J. Phys. Chem. 25,3837 (1971). 49. E. D. -Morrisand C. E. Nordman, Zwg_ Chem. 8,1673 (1969). 60. A. H. Brittain, J. E. Smith, P. L. Lee, K. Cohu, and R. H. Schwendeman, J. A-. Chem. Sot. 93,6772 (1971). 51. G. C. Holywell, D. W. %x&in, B_ Beagley, and J_ M_ Freeman, J_ Chem. Sot_ A. 785 (1971).
it82
J. G. VERKADE
52. P_ Fonti, D. Damiani, and P- G. Favero, J- Amer. CM. SUC.95,756 (1973). 53. While there is evidence pointing to some pi bonding in the BP link in B& adducts of tervalent phosphorus compounds, it is probably small compared to the sigma bonding. See f!25]for a summaxy of this topic. 54. 3. C. Ckd~, R I* KoIpa, and J_ G. Verkade, Phosph, in press. 55 (a) J_ C. Clardy, J. A. Mosbo, and J. G. Verkade, Pho.s@ms, in press; (b) S. Garcis-BIanco and A. Per&es, A&z Cr#uUogr. ZSB, 2647 (1972). 56- EL L. Laube, R. 0. Bertrand, G. k Casedy, R D. Compton, and J. G. Verkade, Inurg. Chem. 6,173 (1967). 57. R. Goetze, H. Noth, and D. S- Payne, Chem. Ber. IO&2637 (1972). 58. S. Fleming, M. K. Lupton, and J. K. Jekot, Inotg. Chem. 11,2%4 (1972). 59. 0. T. BeachleyandT. R Durkin, Inotg. Chem. lZ,1128 (1973)_ 60_ G. Ez McAchran and S. G. Shoie, Inorg. C&n. 5,204% (1966). 61. S. G. Shore, J. L. Crist, B. Lockman, J. R. Long, and A. D. Coon, J_CS. Dalton, 1123 (1972). 62- S. G. Shore, private communication. Rekwd
Augud S&1973; reu&edi’?ovember I.$1973
BIOINORGANZC CHEMISTRY 3, 165-182(1974)
Phosphate
Basicity
Constraint:
The
and Role
Nucleophilicity of the
Alkoxy
Loss
Upon
Oxygerns
J. G. VEXKADE GaYmanHall Deparhent of ChemaNry,Iowa Stak UntierszXy,Ames, Iowa 6ooIO
ABSTRACT Structural evidence is cited which suggests that the POC angle is more flexible than the OPO angle when phosphateesteralkoxygroupsare con-
strainedinto rings. In hybridizationterms, the tendencyfor the POC angieto decrease from ca. 120” in acyclic systems to probably less than li5” in O=P(O)(OCH&CH is consistentwith the notion that an sp” alkoxy oxygen is less capable of pi bonding to phosphorusand consequently
the negative charge on the phosphorus and hence also on the phosphoryl oxygen is dccresed. The &Yerence in orbital co&gurations in acyclic phosphates and in monocyclic and bicyclic analogues has an effect which is seen to re-enforce the hybridization argument. These simple considerations are shown to account for the bulk of the evidence demonstrating that phosphate ester nucleophilicity and bssicity decreases on constraiut of these systems. The “hinge effect” described above for oxygen in phosphates also appears to play a role in varying the basicities of phosphites and also possibly in the acidity changes in certain borate derivates on constraint. Nitrogen apparently also displays a %inge effect” in several amino phospbiue systems. KEY
PHRASES
Phosphate Orbital Symmetries; Cyclic Phosphates and Phosphites; POC Angle Variations in Phosphates and Phosphites; Alkoxy Oxygen “Hinge Effect”; Toxicity.
INTRODUCTION Much evidence has accrued over the past decade regarding the biological of constrained phosphorus heterocycles, such as the cellular
importance
@ AmericanEZsevierPublishing Company, Inc., 1974
_ 180
J. G. VEFtKADE
evidence, results in negative charge concentration on the alkoxy oxygens at the expense of phosphoryl oxygen basicity and phosphorus nucleophilicity.This charge rearrangementbecomes reasonable if the sp* alkoxy oxygens in acyclic phosphates gain p character on constraint, thereby losing pi donating ability to phosphorus. Pi bonding loss is ah indicated by less phosphorusd orbital involvement on symmetry grounds in mono- and bicyclic phosphates compared to acyclic anslogue~. Simikw reasoning can be applied to phosphites. It must be recognized, however, that even though most phosphitesincluding P(OCH2)3C31e are probably strainless, the species of importance in electrophilicattack is four-coordinate, and the phosphorus polarizabiity by the electrophileis dependent on the ease xith which OPO bond angle opening can be achieved, and this property in turn is a function of the degree of constraint. structural
The author thanks the ~Vaticw& Cancer Institule (NIH WSSW& gr~7bt 15969-01) and th.e .Natiunnl Science Foundtiitm (Grant GPSSS 76x) for genewus support of this W&L REFERENCES
AND NOTES
1. F. H. Westheimer, Acwunfs C&R. Res. 1,70 (1968). 2. G. Aksnes and K. Bergesen, Ada Churn.Stand. 20,2508 (1966). 3. F. IF_ Westheimer, in Chimie Organiquedu Phosphore, Centre National de la RechercheScientifique, Paris (1910), p. 307. 4. (a) G. Akmes, private communication, (b) D. W. White and J. G. Verkade, unpublished_ 3. S. C. Goodman and J. G. Verkade, Inmg_ Chem. 5,498 (1966). 6. L. J. Vande Griend, D. W. White, and J. G. Verkade, Phosphorus3,s (1973). 7. (a) A_ L. Mixon and W. R. Gilkerson, J. Phys. Chem. 75, 3309 (1971); (b) J. H. Finley, D. Z Denney, and D. B. Denney, J. Amer. Chem. Sot. 91,5026 (1967). 8. D_ A. Usher, E. A. Dennis, and F. H. Westheimer, J. Amer. Chem. Sot. 87,232O (1965). 9. G_ M. Blackbum, J. S. Cohen, and Lord Todd, TetrahedronL&!ers 2873 (1964). 10. G. I&f.Blackburn, 3. S. Cohen, aud 1. Weatherall, Tefrahedron27,2903 (1971). 11. R L_ Collin, J. Amer- Chem. Sot. 88,3281(1966). 12 D_ Boyd, .J_Amer. Chem. Sot. 91,120O (1969). 13. J. C_ Clardy, D_ Truesdale, and J. G. Verkade, unpublishedrewlts. 14. G. Akmes and R Eriksen, AC&Z Chem. Sand. 20,2463 (1966). 15. (a) R F. Hudson and C. Brown, Accoznk Chem. l&s. 5,204 (1972) and references therein; (b) R. Greenhalgh and R F. Hudson, Phtwplumrs2,l (1972). 16. D. A_ Denney md F. A_ Wagner, Phosphm-us3,27 (1973). 17. D. W. White and J. G. Verkade, Phosphorus3,9 (1973). 18. C. k Streuli, AnuZ. Chem 32,985 (1960)_ 19. E_ M_ Thorsteimon and F. Basolo, J. Amer. Chem. SOC.88,3929 (1966). 20. L. J. Vande Griend and J. G. Verkade, Phm-phams3,13 (1973).
PHOSPHATE
BASICITY
AND
NUCLEOPHILICITY
181
21. R. D. Bertrand, J. G. Verkade, D. W. White, D. Gagmire, J. B. Robert, and J. Verrier, J. &fag_Res. 3,494 (1970). 22. (a) W. Irving, Hooker Chemical Corporation, private communication. @) N. 1. Sax, in Dangerous Properties of Indu&iaZ MabzhZs, Reinhold, New York (1966). 23. (8) R. D. O’Brien, C. Y. Chiu, and J. G. Verkade, unpublished results. @) E. M. E!elIetand J. E. Cssida, private communication. 24. R. L. Keiter and J. G. Verkade, Inerg_ Ch. 9,404 (1970). 25. L. G. Vande Griend and J. G. Verkade, to be published. 26. J. G. Verkade, in Chimfe Organiquedu Phosphore, Centre National de la Recherche ScIentifique, Paris (1970), p. 5. 27. J. G. Verkade, Coord. Chem. Rev. 9,l (1972) and references therein. 28. M. E. Brennan, J_ Chem. Sot_ D, 956 (197O)o). 29. It should not be inferred here that spa lone pair orbit& are necessariiy devoid of pi bonding capability. It has heen shown theoretically (M. J. S. Dewar and P. Rono, J_ A-_ Chem. L&C_91,2!259 (1969)) that pyramidal nitrogens are capable of eonjugating with adjacent unsaturated systems and that the resonance interactions are about four-fifths as effective as planar nitrogen_ If such a pomibiity exists in the case of oxygen in phosphorus esters, the argument would not be altered, however, since the trend would be the same. 30. R. B. Wetzel and G. L. Kenyon, J. Amer. Chem. Sot_ 94,9231 (1972). 31. D. E. C. Corbridge, in Topics in Phosphorus ChemzMy, (M. Grayson and E. J. Griffith, Eds.), Wiley Interscience, New York (1966), p_ 57. 32. D- W. J. Cruikshank, J. Chem. Sot., 5436 (1961). 33. M. G. Newton, J. R. Cox, and J. A. Bertrand, J. A-_ Chem. SOC.88,1503 (1966) and referencestherein_ 34. W. 0. Davies and E. Stanley, Ada Cryslauogr. 15,1OQ2 (1962). 35. (a) D. Swauk, C. N. Caughlan, F_ Ramirez, 0. P. Madan, and C. P. Smith, J. Ave. Chem. Sot. 89, 6603 (1967); (b) T. A. Seits and W. N. Lipscomb, Zbid 87, 2488 (lQ6+ 36. H. J. Geise, Rec. Tran. Chim. 86,362 (1967). 37. D. M. Nimrod, D. R. Fitzwater, and J. G. Verlcade, Znosg. Chim. Acta2,149 (1966). 38. J. C. Clardy, D. C. Dow, and J. G. Verkade, to he published. 39. P. Anderson and K. E. Hjortaas, Aah Chem. Sccmd.14,829 (1960). 40. In the five-membered ring systems and the bicyciic systems the PCC angle is less than 12OO”. Thus, although this p orbital attains some s character in the process, pi bonding is not excluded even though it is diminished (see [26]). 41. E. E. Nifant’ev, A. A. Borisenko, I. S. Nasonovskii, and E. I. Matrosov, DokZ. Akd Nauk USSR I%, 23 (1971) (Engl.). 42. J. A. Mosbo and J. G. Verkade, J. Amer. Chem. Sot. 95,204 (1973). 43. J. A. Mosbo and J. G. Verkade, J. Amer. Chem. Sot., in press. 44. J. Rodgers, D. W. White, and J. G. Verkade, J. Chem. Sot. A, 77 (1971) 45. J. A. Mosbo, J. C. Chudy, and J. G. Verkade, J.C.S. Chem. Cumm., 1163, (1972). 46. L. J. Vande Griend and J. G. Verkade, Znorg. A&Z. Chem. Letfers,9,1137 (1973). 47. D. W. White and J. G. Verkade, Phosphorus 3,15 (1973). 46. J. R. Durig and J. M. Caspar, J. Phys. Chem. 25,3837 (1971). 49. E. D. -Morrisand C. E. Nordman, Zwg_ Chem. 8,1673 (1969). 60. A. H. Brittain, J. E. Smith, P. L. Lee, K. Cohu, and R. H. Schwendeman, J. A-. Chem. Sot. 93,6772 (1971). 51. G. C. Holywell, D. W. %x&in, B_ Beagley, and J_ M_ Freeman, J_ Chem. Sot_ A. 785 (1971).
it82
J. G. VERKADE
52. P_ Fonti, D. Damiani, and P- G. Favero, J- Amer. CM. SUC.95,756 (1973). 53. While there is evidence pointing to some pi bonding in the BP link in B& adducts of tervalent phosphorus compounds, it is probably small compared to the sigma bonding. See f!25]for a summaxy of this topic. 54. 3. C. Ckd~, R I* KoIpa, and J_ G. Verkade, Phosph, in press. 55 (a) J_ C. Clardy, J. A. Mosbo, and J. G. Verkade, Pho.s@ms, in press; (b) S. Garcis-BIanco and A. Per&es, A&z Cr#uUogr. ZSB, 2647 (1972). 56- EL L. Laube, R. 0. Bertrand, G. k Casedy, R D. Compton, and J. G. Verkade, Inurg. Chem. 6,173 (1967). 57. R. Goetze, H. Noth, and D. S- Payne, Chem. Ber. IO&2637 (1972). 58. S. Fleming, M. K. Lupton, and J. K. Jekot, Inotg. Chem. 11,2%4 (1972). 59. 0. T. BeachleyandT. R Durkin, Inotg. Chem. lZ,1128 (1973)_ 60_ G. Ez McAchran and S. G. Shoie, Inorg. C&n. 5,204% (1966). 61. S. G. Shore, J. L. Crist, B. Lockman, J. R. Long, and A. D. Coon, J_CS. Dalton, 1123 (1972). 62- S. G. Shore, private communication. Rekwd
Augud S&1973; reu&edi’?ovember I.$1973