Palladacycles with a metal-bonded sp 3-hybridized carbon as intermediates in the synthesis of 2,2,3,4-tetrasubstituted 2H-1-benzopyrans and 1,2-dihydroquinolines. Effects of auxiliary ligands and substitution at a palladium-bonded tertiary carbon

Organometallics

Volumn 24, Issue 5, 2005, Pages 945-961

  Lu, Genliang ^a   Portscheller, Janelle L ^a   Malinakova, Helena C ^a  

^a UNIVERSITY OF KANSAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DESTABILIZATION; LIGANDS; REACTIVITY; REGIOISOMERS;

CHEMICAL BONDS; DECOMPOSITION; ISOMERS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PALLADIUM COMPOUNDS; SYNTHESIS (CHEMICAL); X RAY CRYSTALLOGRAPHY;

ORGANOMETALLICS;

EID: 14844314189     PISSN: 02767333     EISSN: None     Source Type: Journal    
DOI: 10.1021/om0491544     Document Type: Article

References (85)

1. Diederich, F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling Reactions; Willey-VCH Verlag GmbH: Wenheim, 1998.
2. Palladium-catalyzed asymmetric arylation of ketone, ester, and amide enolates demonstrates the synthetic utility of such strategies, see: (a) Buchwald, S. L.; Hamada, T. Org. Lett. 2002, 4, 999-1001. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (c) Spielvolgel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (e) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
3. Palladium-catalyzed asymmetric arylation of ketone, ester, and amide enolates demonstrates the synthetic utility of such strategies, see: (a) Buchwald, S. L.; Hamada, T. Org. Lett. 2002, 4, 999-1001. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (c) Spielvolgel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (e) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
4. Palladium-catalyzed asymmetric arylation of ketone, ester, and amide enolates demonstrates the synthetic utility of such strategies, see: (a) Buchwald, S. L.; Hamada, T. Org. Lett. 2002, 4, 999-1001. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (c) Spielvolgel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (e) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
5. Palladium-catalyzed asymmetric arylation of ketone, ester, and amide enolates demonstrates the synthetic utility of such strategies, see: (a) Buchwald, S. L.; Hamada, T. Org. Lett. 2002, 4, 999-1001. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (c) Spielvolgel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (e) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
6. Palladium-catalyzed asymmetric arylation of ketone, ester, and amide enolates demonstrates the synthetic utility of such strategies, see: (a) Buchwald, S. L.; Hamada, T. Org. Lett. 2002, 4, 999-1001. (b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (c) Spielvolgel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500-3501. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-3415. (e) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
7. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
8. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
9. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
10. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
11. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
12. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
13. 2 failed to occur, see: (e) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5749-5752. However, nickel-catalyzed coupling to secondary alkyl halides is known, see: (f) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
14. 3-hybridized carbon has been invoked to rationalize these observations, a recent theoretical study pointed to a significant contribution from electronic factors, demonstrating stabilization of alkyl organometallics arising from the presence of an electron-withdrawing group at the metal-bonded carbon, see: (e) Harvey, J. N. Organometallics 2001, 20, 4887-4895.
15. 3-hybridized carbon has been invoked to rationalize these observations, a recent theoretical study pointed to a significant contribution from electronic factors, demonstrating stabilization of alkyl organometallics arising from the presence of an electron-withdrawing group at the metal-bonded carbon, see: (e) Harvey, J. N. Organometallics 2001, 20, 4887-4895.
16. 3-hybridized carbon has been invoked to rationalize these observations, a recent theoretical study pointed to a significant contribution from electronic factors, demonstrating stabilization of alkyl organometallics arising from the presence of an electron-withdrawing group at the metal-bonded carbon, see: (e) Harvey, J. N. Organometallics 2001, 20, 4887-4895.
17. 3-hybridized carbon has been invoked to rationalize these observations, a recent theoretical study pointed to a significant contribution from electronic factors, demonstrating stabilization of alkyl organometallics arising from the presence of an electron-withdrawing group at the metal-bonded carbon, see: (e) Harvey, J. N. Organometallics 2001, 20, 4887-4895.
18. 3-hybridized carbon has been invoked to rationalize these observations, a recent theoretical study pointed to a significant contribution from electronic factors, demonstrating stabilization of alkyl organometallics arising from the presence of an electron-withdrawing group at the metal-bonded carbon, see: (e) Harvey, J. N. Organometallics 2001, 20, 4887-4895.
19. Malinakova, H. C. Chem. Eur. J. 2004, 10, 2636-2646.
20. Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 3rd ed., John Wiley and Sons: New York, 2001; Chapter 4.
21. 2 to be 129.6° and 101.5°, respectively. Thus, the distortion of the square planar geometry (deviation from P-Pd-P angle 90°) appears to arise from the notable steric bulk of the phosphine ligands.
22. see: (b) Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-387.
23. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
24. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
25. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
26. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
27. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
28. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
29. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
30. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
31. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
32. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
33. For representative examples of preparations of stable late transition metal enolates and other complexes bearing an electron-withdrawing substituent at the metal-bonded carbon, see: (a) Heath-cock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, U. K., 1991; Vol. 2, Chapter 1.9. (b) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem. Soc. 2002, 124, 6842-6843. (c) Ryabov, A. D.; Panyashkina, I. M.; Polyakov, V. A.; Fisher, A. Organometallics 2002, 21, 1633-1636. (d) Kujime, M.; Hikichi, S.; Akita, M. Organometallics 2001, 20, 4049-4060. (e) Hashmi, S. K. A.; Naumann, F.; Bolte, M. Organometallics 1998, 17, 2385-2387. (f) Vicente, J.; Abad, J. A.; Chicote, M.-T.; Abrisqueta, M.-D.; Lorca, J.-A.; Ramirez de Arelano, M. C. Organometallics 1998, 17, 1564-1568. (g) Rasley, B. T.; Rapta, M.; Kulawiec, R. J. Organometallics 1996, 15, 2852-2854. (h) Garcia-Ruano, J. L.; Gonzalea, A. M.; Barcena, A. I.; Camazon, M. J.; Navarro-Ranninger, C. Tetrahedron: Asymmetry 1998, 7, 139-148. (i) Hartwig, J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1990, 112, 5670-5671. (j) Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1988, 60, 1-6. (k) Weinstock, I.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem. Soc. 1966, 108, 8298-8299.
34. (a) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398-3416.
35. (b) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-5817.
36. For the discussion of the different bonding modes available to palladium enolates, see: (a) Tian, G.; Boyle, P. D.; Novak, B. M. Organometallics 2002, 21, 1462-1465. (b) Albeniz, A. C.; Catalina, N. M.; Espinet, P.; Redon, R. Organometallics 1999, 18, 5571-5576. Reference 9a, and references therein. (c) In general, for late transition metal enolates, coordination to palladium through the carbon atom is preferred, see ref 10b.
37. For the discussion of the different bonding modes available to palladium enolates, see: (a) Tian, G.; Boyle, P. D.; Novak, B. M. Organometallics 2002, 21, 1462-1465. (b) Albeniz, A. C.; Catalina, N. M.; Espinet, P.; Redon, R. Organometallics 1999, 18, 5571-5576. Reference 9a, and references therein. (c) In general, for late transition metal enolates, coordination to palladium through the carbon atom is preferred, see ref 10b.
38. For the discussion of the different bonding modes available to palladium enolates, see: (a) Tian, G.; Boyle, P. D.; Novak, B. M. Organometallics 2002, 21, 1462-1465. (b) Albeniz, A. C.; Catalina, N. M.; Espinet, P.; Redon, R. Organometallics 1999, 18, 5571-5576. Reference 9a, and references therein. (c) In general, for late transition metal enolates, coordination to palladium through the carbon atom is preferred, see ref 10b.
39. (a) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 8266-8279.
40. (b) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 4701-4715.
41. (c) Portscheller, J. L.; Lilley, S. E.; Malinakova, H. C. Organometallics 2003, 22, 2961-2971.
42. (d) Portscheller, J. L.; Malinakova, H. C. Org. Lett. 2002, 4, 3679-3681.
43. For examples of biologically active 2,2-disubstituted 2H-1-benzopyrans, see: (a) Yu, L. J. Agric. Food Chem. 2003, 51, 2344-2347. (b) Shin, H. S.; Seo, H. W.; Yoo, S. E.; Lee, B. H. Pharmacology 1998, 56, 111-124. (c) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.; Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.; Atwal, K. S.; Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph, P. G.; Traeger, S. C. J. Med. Chem. 1997, 40, 24-34. For examples of biologically active 2,2-disubstituted 1,2-dihydroquinolines, see: (d) Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.; Mao, Y.; Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.; Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.; Lane, B. Bioorg. Med. Chem. Lett. 2004, 14, 1721-1727.
44. For examples of biologically active 2,2-disubstituted 2H-1-benzopyrans, see: (a) Yu, L. J. Agric. Food Chem. 2003, 51, 2344-2347. (b) Shin, H. S.; Seo, H. W.; Yoo, S. E.; Lee, B. H. Pharmacology 1998, 56, 111-124. (c) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.; Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.; Atwal, K. S.; Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph, P. G.; Traeger, S. C. J. Med. Chem. 1997, 40, 24-34. For examples of biologically active 2,2-disubstituted 1,2-dihydroquinolines, see: (d) Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.; Mao, Y.; Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.; Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.; Lane, B. Bioorg. Med. Chem. Lett. 2004, 14, 1721-1727.
45. For examples of biologically active 2,2-disubstituted 2H-1-benzopyrans, see: (a) Yu, L. J. Agric. Food Chem. 2003, 51, 2344-2347. (b) Shin, H. S.; Seo, H. W.; Yoo, S. E.; Lee, B. H. Pharmacology 1998, 56, 111-124. (c) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.; Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.; Atwal, K. S.; Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph, P. G.; Traeger, S. C. J. Med. Chem. 1997, 40, 24-34. For examples of biologically active 2,2-disubstituted 1,2-dihydroquinolines, see: (d) Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.; Mao, Y.; Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.; Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.; Lane, B. Bioorg. Med. Chem. Lett. 2004, 14, 1721-1727.
46. For examples of biologically active 2,2-disubstituted 2H-1-benzopyrans, see: (a) Yu, L. J. Agric. Food Chem. 2003, 51, 2344-2347. (b) Shin, H. S.; Seo, H. W.; Yoo, S. E.; Lee, B. H. Pharmacology 1998, 56, 111-124. (c) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.; Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.; Atwal, K. S.; Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph, P. G.; Traeger, S. C. J. Med. Chem. 1997, 40, 24-34. For examples of biologically active 2,2-disubstituted 1,2-dihydroquinolines, see: (d) Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.; Mao, Y.; Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.; Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.; Lane, B. Bioorg. Med. Chem. Lett. 2004, 14, 1721-1727.
47. Gribble, G. W., Gilchrist, T. L. Eds. Progress in Heterocyclic Chemistry; Pergamon: Oxford, 2001; Vol. 13.
48. Ramakrishnan, V. R.; Kagan, J. J. Org. Chem. 1970, 35, 2901-2904.
49. -1, see ref 11d.
50. 1 = Ph).
51. 3), see ref 11d.
52. For the synthesis of stable three-coordinate arylpalladium halide and arylpalladium amido complexes featuring one sterically demanding phosphine ligand, see: (a) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344-5345. (b) Stambuli, J. P.; Bühl, M.; Hartwig, J. P. J. Am. Chem. Soc. 2002, 124, 9346-9347. Involvement of dimeric arylpalladium halide complexes with a single sterically demanding phosphine ligand as intermediates in palladium-catalyzed cross-coupling reactions has been proposed, see: (c) Galardon, E.; Ramdeehul, J. M.; Brown, J. M.; Cowley, A.; Kuok, K. H.; Jutand, A. Angew. Chem., Int. Ed. 2002, 41, 1760-1763.
53. For the synthesis of stable three-coordinate arylpalladium halide and arylpalladium amido complexes featuring one sterically demanding phosphine ligand, see: (a) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344-5345. (b) Stambuli, J. P.; Bühl, M.; Hartwig, J. P. J. Am. Chem. Soc. 2002, 124, 9346-9347. Involvement of dimeric arylpalladium halide complexes with a single sterically demanding phosphine ligand as intermediates in palladium-catalyzed cross-coupling reactions has been proposed, see: (c) Galardon, E.; Ramdeehul, J. M.; Brown, J. M.; Cowley, A.; Kuok, K. H.; Jutand, A. Angew. Chem., Int. Ed. 2002, 41, 1760-1763.
54. For the synthesis of stable three-coordinate arylpalladium halide and arylpalladium amido complexes featuring one sterically demanding phosphine ligand, see: (a) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344-5345. (b) Stambuli, J. P.; Bühl, M.; Hartwig, J. P. J. Am. Chem. Soc. 2002, 124, 9346-9347. Involvement of dimeric arylpalladium halide complexes with a single sterically demanding phosphine ligand as intermediates in palladium-catalyzed cross-coupling reactions has been proposed, see: (c) Galardon, E.; Ramdeehul, J. M.; Brown, J. M.; Cowley, A.; Kuok, K. H.; Jutand, A. Angew. Chem., Int. Ed. 2002, 41, 1760-1763.
55. 3), e.g., [4]:L = 1:2, would be expected for a complete conversion to palladacycles [4] with two phosphine ligands per palladium atom (complexes [4a] and [4c]), and a ratio of [4]:L = 1:3 would be expected for a complete conversion to palladacycle [4e] with a single phosphine ligand per palladium.
56. Tollman, C. A. Chem. Rev. 1977, 77, 313-348.
57. 1H NMR spectra confirmed the presence of 0%, 3%, and 4% of unreacted complexes 3a, 3c, and 3d, in the crude reaction mixtures corresponding to spectra b, d, and f in Scheme 2, respectively.
58. 3 solution.
59. a for esters of 2-phenoxycarboxylic acids, see: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
60. 31P NMR spectra of complexes 5-8 reveal second-order AB patterns for the two nonequivalent and strongly coupled phosphorus atoms with a significant "roofing effect". As a consequence, in the spectra of complexes 5a, 6a, and 8a, the weak "outer" signals could not be detected, and only two singlet signals could be reported.
61. 2Me), respectively.
62. 3) as a stable fully characterized product in 86% yield, see ref 11d.
63. 3. However, a partial oxidation of air-sensitive phosphine ligands and/or partial decomposition of the semistable organopalladium complexes could not be avoided under these conditions.
64. 1 (Ph) could partially offset the unfavorable steric factors by its electron-withdrawing effects, see refs 4d and 9a.
65. 2Me, in the molar ratio 8e:[4g]:L = 0:87:13. However, isolation and complete characterization of palladacycle [4g] were not attempted.
66. The IR spectra of the crude reaction mixtures were measured in neat films generated upon evaporation of methylene chloride solvent on the surface of NaCl salt plates.
67. -1 for L-L = 1,2-bis(diphenylphosphino) ethane (dppe), see refs 11c and 11d.
68. 2, L-L = 1,2-bis(diphenylphosphino)butane (dppb)) facilitated the insertion of dmad, providing the corresponding benzopyran in a good yield (64%), see ref 11d.
69. For the discussion of the mechanism and the origins of regiocontrol in alkyne insertion reactions with group 10 metalacycles, see: (a) Bennet, M. A.; Macgregor, S. A.; Wenger, E. Helv. Chim. Acta 2001, 84, 3084-3104. (b) Campora, J.; Palma, P.; Carmona, E. Coord. Chem. Rev. 1999, 193-195, 207-281.
70. For the discussion of the mechanism and the origins of regiocontrol in alkyne insertion reactions with group 10 metalacycles, see: (a) Bennet, M. A.; Macgregor, S. A.; Wenger, E. Helv. Chim. Acta 2001, 84, 3084-3104. (b) Campora, J.; Palma, P.; Carmona, E. Coord. Chem. Rev. 1999, 193-195, 207-281.
71. 2EtN, see: Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
72. 4 under the conditions described in Scheme 5 for 24 h did not give rise to the corresponding benzopyran in concentrations detectable by TLC.
73. The addition of 1,2-dichloroethane (DCE) (6 mL) solvent into the THF (1 mL) solutions of the reactants allowed performing the alkyne insertion reaction under reflux at elevated temperatures. Furthermore, the decrease in overall solvent polarity in the DCE/THF mixtures would be expected to favor migratory insertion of alkynes into palladacycles of type [4].
74. The additions of alkyne solutions into the reaction mixtures containing arylpalladium(II) iodo complexes 5-8 were delayed 20-40 min following the introduction of t-BuOK, to allow for the ring closure to occur and to consume the t-BuOK, and thus avoid possible base-induced side-reactions between a full equivalent of base (t-BuOK) and the alkynes.
75. 1H NMR NOE analysis of benzopyran 12 indicated that irradiation of the signal for the proton in the methyl group attached to C-4 position at δ 2.26 (s) led to the NOE enhancement of the signal for the proton at C-5 in the aromatic ring at δ 7.31 (dd). NOE H Me COOEt Et O COOEt 12
76. 13C correlations revealed by HMBC 2D NMR spectroscopic analysis was complicated due to the overlap of both the proton and carbon signals for protons and carbons from the two aromatic rings.
77. 1H NMR.
78. (a) An alternative pathway consisting of a migratory insertion of the alkyne into palladium(II) complexes 5-8 and subsequent displacement of the anionic iodide ligand providing seven-membered palladacycles, which would undergo a reductive elimination, might also account for the formation of benzopyrans 9-17. Most likely, the extent of this process would be limited to the portion of complexes 5-8 that failed to provide palladacycles [4] within the initial 20-40 min period of treatment with t-BuOK. The formation of palladacycles [4] could continue after the addition of alkynes, and thus simultaneous operation of both these pathways cannot be ruled out. For examples of studies exploring insertion of unsaturated molecules into stable arylpalladium(II) halide complexes yielding heterocyclic products, see: (b) Vicente, J.; Abad, J.-A.; Lopez-Serrano, J.; Jones, P. G. Organometallics 2004, 23, 4711-4722. (c) Vicente, J.; Abad, J.-A.; Fortsch, W.; Lopez-Saez, M. J.; Jones, P. G. Organometallics 2004, 23, 4414-4429.
79. (a) An alternative pathway consisting of a migratory insertion of the alkyne into palladium(II) complexes 5-8 and subsequent displacement of the anionic iodide ligand providing seven-membered palladacycles, which would undergo a reductive elimination, might also account for the formation of benzopyrans 9-17. Most likely, the extent of this process would be limited to the portion of complexes 5-8 that failed to provide palladacycles [4] within the initial 20-40 min period of treatment with t-BuOK. The formation of palladacycles [4] could continue after the addition of alkynes, and thus simultaneous operation of both these pathways cannot be ruled out. For examples of studies exploring insertion of unsaturated molecules into stable arylpalladium(II) halide complexes yielding heterocyclic products, see: (b) Vicente, J.; Abad, J.-A.; Lopez-Serrano, J.; Jones, P. G. Organometallics 2004, 23, 4711-4722. (c) Vicente, J.; Abad, J.-A.; Fortsch, W.; Lopez-Saez, M. J.; Jones, P. G. Organometallics 2004, 23, 4414-4429.
80. (a) An alternative pathway consisting of a migratory insertion of the alkyne into palladium(II) complexes 5-8 and subsequent displacement of the anionic iodide ligand providing seven-membered palladacycles, which would undergo a reductive elimination, might also account for the formation of benzopyrans 9-17. Most likely, the extent of this process would be limited to the portion of complexes 5-8 that failed to provide palladacycles [4] within the initial 20-40 min period of treatment with t-BuOK. The formation of palladacycles [4] could continue after the addition of alkynes, and thus simultaneous operation of both these pathways cannot be ruled out. For examples of studies exploring insertion of unsaturated molecules into stable arylpalladium(II) halide complexes yielding heterocyclic products, see: (b) Vicente, J.; Abad, J.-A.; Lopez-Serrano, J.; Jones, P. G. Organometallics 2004, 23, 4711-4722. (c) Vicente, J.; Abad, J.-A.; Fortsch, W.; Lopez-Saez, M. J.; Jones, P. G. Organometallics 2004, 23, 4414-4429.
81. Bergeron, R. J.; Hoffman, P. J. Org. Chem. 1980, 45, 161-163.
82. (a) Crich, D.; Sannigrahi, M. Tetrahedron 2002, 58, 3319-3322.
83. (b) Ko, S. S.; Confalone, P. N. Tetrahedron 1985, 41, 3611-3518.
84. 1H NOE NOE analysis of 1,2-dihydroquinoline 22 indicated that irradiation of the signal for the proton in the methyl group attached to the C-4 position at δ 2.22 (s) led to the NOE enhancement of the signal for the proton at C-5 in the aromatic ring at δ 7.37 (d). NOE H Me COOEt Me N COOEt COOMe 22
85. f = 0.38 in TLC (EtOAc/hexanes, 1:3). It is conceivable that as a result of a restricted rotation, complex 8c exists as two chromatographically separable conformational isomers. The observed difference in the appearance of NMR spectra of the two conformational isomers reflects the difference in the degree of rotational freedom in each isomer.