本論文藉由理論計算的方法，討論具有胜肽鍵型態HNC=O的兩個分子(Hydroxamic acid及N-Nitrosoamides)的重要反應，分別是HAs及其衍生物的甲基化反應，及N-Nitrosoamides的熱分解反應。共分為三個單元進行討論：
第一部分： 研究兩種不同構形的HAs甲基化的反應路徑及取代基的效應，Z form的HAs甲基化反應共有七條可能的路徑，分別形成氧甲基及氮甲基的衍生物，經由Path Z7形成O-O雙甲基取代產物9活化能最低(能障17.24 kcal/mol)，將C上的H分別以CH3,Cl,CHCH2取代後，會降低某些特定反應路徑的活化能，生成N甲基取代的產物6的機率可以大大提升。
E form的HAs甲基化反應有6條可能的路徑，會經由兩條能障較低的反應路徑Path E5、E6(能障各為22.85 kcal/mol、23.06 kcal/ mol)，得到O,O雙甲基取代的產物24，產物同樣有高的位置選擇性，將C上的H分別以CH3,Cl,CHCH2取代後，僅Cl取代會改變瓶頸反應進行之路徑，產物的位置選擇性並不會受到取代基的影響，E form的甲基化反應得到N甲基取代的產物27，其活化能相對較高。
第二部分： 研究Thiohydroxamic acid(SHAs)並與Hydroxamic acid做比較，結果發現反應的相對能量、過渡狀態的結構，及反應進行的路徑都會受到S取代的影響而有明顯地不同，O和S原子體積的大小及電負度的差異是兩大主因，但是不論是Z form或是E form的SHAs甲基化反應，產物都有高的位置選擇性，生成N甲基取代的產物其活化能相對較高，這是和HAs相似。
第三部分： 研究N-Nitrosoamides的熱分解反應，討論取代在兩個不同取代位置(N及C上)對熱分解反應的影響，研究中設計了兩個isodesmic reaction幫助我們更進一步了解取代基的作用，結果發現相同的取代基取代在這兩個不同位置有很不一樣的效應，且取代在C位置比起取代在N位置有較顯著的電子效應、立體效應及氫鍵的效應，以SiH3取代後甚至會有不同的反應路徑產生。
N-Nitrosoamides的熱分解反應在酸的催化下，會進行deaminative (-N2)及denitrosative (-NO+)的競爭反應，從我們推出的反應機構中可以得知反應如何受到酸度、溫度及親核試劑的加入所影響。

We carried out theoretical studies for two important reactions involving HNCO peptide bond: 1. the methylation of Hydroxamic Acid (RC(=X)NHOH, X=O、R=H) and its derivatives (X=S、R=CH3,Cl,CHCH2) with diazomethane , and 2. the thermal deamination and denitrosation of N-Nitrosoamides . The descriptions are following:
Part 1： There are seven possible pathways of methylation of (Z)HAs to generate O-alkylation and N-alkylation products. Path Z7 generating (Z)O,O-dimethylhydroxamates 9 has the lowest energy barrier 17.24 kcal/mol. The reaction between HAs and CH2N2 results in predominant formation of product 9 strictly high-site selective. When the substitutents of CH3, Cl and CHCH2 are added, the energy barrier of pathways and the site selection of product will be affected. The probability for the formation of (Z)N,O-dimethylhydroxamates 6 will be increase.
There are six possible pathways in the E-form Has methylation. Path E5、E6 generate (E)O,O-dimethylhydroxamate 24 , with the energy barriers, 22.85 kcal/mol, and 23.06 kcal/mol respectively. The substituents CH3, Cl and CHCH2 have little effect to the site-selectivity of the products except the Cl-substituent changes the rate-determine step. The production of (E)N,O-dimethylhydroxamates 27 has higher energy barrier.
Part 2： The similar methylation reaction of thiohydroxamic acid is investigated and the result compared with that of hydroxamic counterparts. We found that the relative energies、structures of transition state and the pathways of reaction were affected by two major factors: the size and the electronegativity of O and S atom. However products of Z and E isomers of SHAs also have high site-selectivity , with N-methyl product obtained at higher barrier, similar to Has counterparts.
Part 3： We studied theoretical the thermal decomposition of N-Nitrosoamides and designed two isodesmic reaction to understand the substitutions effects on the stability of the reactant and transition state . We found that the substitution at the different sites (N and C) of N-Nitrosoamides led to very different results. The silyl substituent at C-site even followed different pathway of decomposition.
The thermal decomposition of N-Nitrosoamides in acidic condition may undergo deaminative (loss of N2) and denitrosative (loss of NO+) two competitive pathways. According to our result, we may understand how the acidity, temperature and added nucleophilicity affect reaction barriers.

(1) Lossen, H. ; Liebigs J. Ann. Chem. 1869, 150, 314.
(2) Munson, J. W. Hydroxamic Acids In The Chemistry of Acid Derivatives; Patai, S., Ed.; J. Wiley and Sons: New York, 1992; Suppl. B, Vol. 2, p 849.
(3) Miller, M. J. Chem. Rev. 1989, 89, 1563.
(4) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376.
(5) Srewart, A. O.; Martin, G. J. J. Org. Chem. 1989, 54, 1221.
(6) Christianson, D. W. Adv. Protein Chem. 1991, 42, 281-355
(7) (a)Sobolewski, A. L. J. Photochem. Photobiol. A:Chemistry, 1995, 89(2), 89. (b) Lowdin, P. O. Rev. Med. Phys. 1963,35,724.
(8) (a) Mizukami, S. ; Nagata, K. C. Chem. Rev., 1968, 3, 267 (b) King ,T.J. ; Harrison, P.G. J. Chem. Soc., Chem. Commun. 1972, 13 , 815 (c)Michaelson, R.C.; Palermo, R.E.; Sharpless, K.B. J. AM. Chem. Soc., 1977. 99. 1990.
(9) (a) Musser, J. H.; Kreft, A. F.; Bender, R. H. W.; Kubrak, D. M.; Grimes, D.; Carlson, R. P.; Hand, T. M.; Chang, J. J. Med. Chem. 1990, 33, 240. (b) Summers, J.B.; Gunn, B.P. ; Martin, J, G.; Martin, M. B.; Mazdiyasni, H. ; Stewart, A. O.; Young, P. R.; Bouska, J. B. ; Goetze, A. M.; Dyer, R. D. ; Brooks, D. W. ; Carter, G. W. J. Med. Chem. 1988,31, 1960-1964 (c) Huang, F. C.; Scott Shoupe, T. ; Lin, C. J. ; Lee, D. Y.; Chan, W. K.; Tan, J.; Schnapper, M, ; Suh, J. T. ; Gordon, R. J.; Sonnino, P. A.; Sutherland, C. A.; Van Inwegen, R. G. ; Coutts'l, S. M. J . Med. Chem. 1989, 32, 1836-1842 (d) Summers, J. B.; Kim, K. H.; Mazdiyasni, H.; Holms, J. H. ; Ratajczyk, J. D. Stewart, A. O. ; Dyer, R. D. ; Cartert, G. W. J. Med. Chem. 1990, 33, 992-998
(10) Leggio, A.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G. J. Org Chem. 2001, 66, 2246
(11) (a) Yen, S-.J., Lin, C-.Y. Ho, J-.J. J. Phys. Chem. A 2000, 104, 11771-11776 (b) Yen, S-.J., Ho J-.J. J. Phys. Chem. A 2000, 104, 8557 (c) Wu, D-.H.; Ho, J-.J. J. Phys. Chem. 1998, 102, 3582.
(12) Turi, L. ; Damenberg, J. J. ; Rama, J.; Ventura, O. N. J. Phys. Chem. 1992. 96. 3709-3712
(13) Brown, D.A. ; Glass, W.K. ; Mafeswaran, R. ; Girmay, B. Magn. Reson. Chem., 1988, 26, 970
(14) Larsen, I.K. Acta Crystallogr., Sect. B, 1988, 44, 527
(15) Plapinger, R. E. J. Org. Chem. 1959, 24, 802
(16) Exner, O.; Kakac. B. Collect. Czech. Chem. Commun. 1963, 28, 1656.
(17) Ventura, O. N.; Rama, J. B.; Turi, L.; Dannenberg, J. J. J. Am. Chem. Soc. 1993, 115, 5754.
(18) Reed, A. E.; Weinstock, R. B.; Weinhold, F. A. J. Chem. Phys.1985, 83, 735.
(19) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1985, 83, 1786.
(20) Reed, A. E.; Schleyer, P. V. R. J. Am. Chem. Soc. 1990, 112, 1434.
(21) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. The NBO program, Version 3.1.
(1) Walter, W.; Schaumann, E. Synthesis 1971, 111 and reference therein
(2) Mitchell, A. J.; Murray, K. S.; Newman, P. J.; Clark, P. E. Aust. J.
Chem. 1977, 30, 2439.
(3) Rupprecht, S.; Langemann, K.; Lügger, T.; McCormick, J. M.;
Raymond, K. N. Inorganica Chimica Acta 1996, 243, 79-90 and
reference therein
(4) Nagata, K.; Mizukami, S. Chem. Pharm. Bull. 1996, 14, 1255
(5) Jensen, K.A.; Buchardt, O.; Christophersen, C. Actahem.Scand.1967,
21, 1936.
(6) Sekhon, E.; Dissertation, Universitat Hamburg, 1970.
(7) Yen, S.J. ; Ho, J.J. J. Phys. Chem. A 2000, 104, 8551-8557
(8) (a) Yen, S.J. ; Lin, C.Y. ; Ho, J.J. J. Phys. Chem. A 2000, 104, 11771-
11776 (b) Wu, D.H.; Ho, J.J. J. Phys. Chem. 1998, 102, 3582.
(9) Ou, M. C. ;Tsai, M. S. ; Chu, S. Y. J. Mol. Struct. 1994, 310, 247.
(10) Wiberg, K. B. ;Rablen, P. R. J. Am. Chem. Soc. 1995, 117, 2201.
(1) (a) Lee, K.; Gold, B.; Mirvish, S. Mutat. Res. 1977, 48, 131. (b)
Preussman, R.; Stewart, B. W. Chemical Carcinogenesis; Searle, C.,Ed.,
ACS Monograph No. 182, American Chemical Society, Washington,DC,
1984; p 643. (c) White, E. H.; Jelinski, L. W.; Politzer, I. R.;Branchini, B.
R.; Roswell, D. R. J. Am. Chem. Soc. 1981, 103, 4231.(d) Darbeau, R. W.;
Delaney, M. S.; Ramelow, U.; James, K. R. Org.Lett. 1999, 1 (5) 796. (e)
White, E. H.; De Pinto, J. T.; Polito, A. J.;Bauer, I.; Roswell, D. F. J. Am.
Chem. Soc. 1988, 110, 3708. (f)Darbeau, R. W.; White, E. H. J. Org.
Chem. 1997, 62, 8091. (g)Darbeau, R. W.; White, E. H.; Nunez, N.; Coit,
B.; Daigle, M. J. Org.Chem. 2000, 65, 1115. (h) White, E. H.; Darbeau, R.
W.; Chen, Y.; Chen,D.; Chen, S. J. Org. Chem. 1996, 61, 7986. (i)
Darbeau, R. W.; White,E. H. J. Org. Chem. 2000, 65, 1121. (j) M.S.
Thesis by Rebekah E.Gibble, 2001, McNeese State University, Lake
Charles, LA. (k) Previously referred to as nitrogenous molecule-separated
ion-pairs and inert molecule-separated ion-pairs (NSIPs and IMSIPs,
respectively).1d,f,g-i
(2) (a) White, E. H.; De Pinto, J. T.; Polito, A. J.; Bauer, I.; Roswell,D. F. J.
Am. Chem. Soc. 1988, 110, 3708. (b) White, E. H.; Field, K.W.;
Hendrickson, W. H.; Dzadzic, P.; Roswell, D. F.; Paik, S.; Mullen, P. W. J.
Am. Chem. Soc. 1992, 114, 8023. (c) White, E. H.; McGirk, R. H.;
Aufdermarsh, C. A.; Tiwari, H. P.; Todd, M. J. J. Am. Chem. Soc.1973, 95,
8107. (d) White, E. H.; Dolak, L. A. J. Am. Chem. Soc. 1966,88, 3790.
(3) (a) Kirmse, W. J.; Moench, D. Chem. Ber. 1991, 124, 4 (1), 237. (b)
Brosch, D.; Kirmse, W. J. J. Org. Chem. 1991, 56 (3), 907. (c) Huisgen,
R.; Ruchardt, C. Justus Liebigs Ann. Chem. 1956, 601, 1. (d) Wiberg, K.
B.; Osterle, C. G. J. Org. Chem. 1999, 64, 7756. (e) Wiberg, K. B.;Osterle,
C. G. J. Org. Chem. 1999, 64, 7763. (f) Wiberg, K. B.; Shobe, D. S. J.
Org.Chem. 1999, 64, 7768. (g) Laughlin, R. G. J. Am.Chem. Soc. 1967,
89, 4268. (h) Huisgen, R.; Ruchardt, C. Justus LiebigsAnn. Chem. 1956,
601, 1.
(4) (a) Darbeau, R. W.; Pease, R. S.; Gibble, R. E. J. Org. Chem. 2001, in
press. (b) White, E. H.; Darbeau, R. W.; Chen, D.; Chen, S.; Chen, Y. J.
Org. Chem. 1996, 61, 7986. (c) Darbeau, R. W.; White, E. H. J. Org.
Chem. 1997, 62, 8091. (d) Darbeau, R. W.; White, E. H.;Song, F.;
Darbeau, N. R.; Chou, J. C. J. Org. Chem. 1999, 64 (16), 5966. (e)
Darbeau, R. W.; Delaney, M. S.; Ramelow, U.; James, K. R. Org.Lett.
1999, 1 (5), 796. (f) Darbeau, R. W.; White, E. H.; Nunez, N.;Coit, B.;
Daigle, M. J. Org. Chem. 2000, 65, 1115. (g) Darbeau, R. W；White, E. H.
J. Org. Chem. 2000, 65, 1121. (h) Song, F.; Darbeau, R.W.; White, E. H.
J. Org. Chem. 2000, 65, 1825. (i) Darbeau, R. W；Perez, E.V.; Sobieski,
J.I.; Rose, W. I.; Yates, M.C.; Boese, B. J.; Darbeau, N. R. J. Org. Chem.
2001, 66, 5679-5686
(5) (a) Moss, R. A. J. Org. Chem. 1966, 31, 1082. (b) Moss, R. A.
Chem. Eng. News 1971, 49 (48), 28. (c) Moss, R. A. Acc. Chem. Res.
1974, 7, 421. (d) Moss, R. A. Acc. Chem. Res. 1980, 13, 58. (e) Moss, R.
A. Acc. Chem. Res. 1989, 22, 15. (f) Moss, R. A.; Grover, E. R. J. Org.
Chem. 1976, 41, 1128. (g) Moss, R. A.; Joyce, M. A. J. Am. Chem. Soc.
1978, 100, 4475. (h) Moss, R. A.; Landon, M. J. J. Am. Chem. Soc.
1970, 92, 5755. (i) Moss, R. A.; Lane, S. M. J. Am. Chem. Soc. 1967,
89, 3655.
(6) (a) Berry, C. N.; Challis, B. C. J. Chem. Soc., Perkin Trans. 2
1974, 1638. (b) Challis, B. C.; Jones, S. P. J. Chem. Soc., Perkin Trans.
2 1975, 153.
(7) (a) Williams, D. L. H. J. Chem. Soc., Perkin Trans. 2 1975, 655.
(b) Williams, D. L. H. J. Chem. Soc., Perkin Trans. 2 1976, 1838.
(8) (a) Huisgen, R.; Ruchardt, C. Justus Liebigs Ann. Chem. 1956, 601, 1.
(b) White, E. H.; Dolak, L. A. J. Am. Chem. Soc. 1966, 88, 3790.
(9) Ph.D. Thesis by Ron W. Darbeau, 1996, The Johns Hopkins University,
Baltimore, Maryland.
(10) Vladimir Benin,†,‡ Piotr Kaszynski,*,† and J. George Radziszewski§, J.
Am. Chem. Soc. 2002, 124, 14115-14126
(11) (a)Martinez, F. N.; Schegel, H. B.; Newcomb, M. J. Org. Chem. 1998,
63, 3618. (b) Sun Y., Wong M. W., J. Org. Chem. 1999, 64, 9170-9174(c)
Pascal F., Robert L. M., Richard F.;J. Phys. Chem. 1986, 90(22); 5571-
5573. (D)Hehre, W. J.; Ditchfield, R.; Radomm, L.; Pople, J. A. J. Am.
Chem. Soc. 1970, 92, 4796
(12) Apeloig,Y.；Arad, D.；Rappoport,Z. J. Am. Chem. Soc. 1990, 112,
9131-9140
(13) Alem, K. V. ; Lodder, G. J. Phys. Chem. A. 2002, 106, 10681-10690