Substituent effect on the efficiency of desulfurizative rearrangement of allylic disulfides.
Crich ligation is a new method for the functionalization of peptides and proteins under mild conditions. To more fully understand the mechanism of the ligation and to explore the effect of substitution on its efficiency, a systematic theoretical study is carried out for the first time. It is found that the MP2 method wrongly predicts the substituent effect whereas the ONIOM(CCSD(T):B3LYP) method overestimates the free energy barriers by ca. 4 kcal/mol. Only the ONIOM(G3B3:B3LYP) method is found to be reliable as well as feasible for studying the ligation. The rate-limiting step of the ligation is found to be the [2,3]-sigmatropic rearrangement of the alkyl allyl disulfide, followed by an S N2 phosphine-mediated desulfurization. The S-S bond is significantly polarized during the rearrangement and, therefore, the reaction proceeds more rapidly in polar solvents. R S and R 3 substitutions elevate the free energy barrier of the ligation, whereas the R 2 substitution does not exert a useful effect. Only the substitution at R 1 can effectively reduce the free energy barrier of the reaction to less than 20 kcal/mol (a value required to allow the reaction to complete in minutes at 25 degrees C). Therefore, secondary and tertiary allyl alkyl disulfides can undergo the ligation at the room temperature. Marcus theory analysis indicates that the major factor for the retardation of the reaction by substituents at R S and R 3 and for the acceleration by substituents at R 1 is the thermodynamic equilibrium between the disulfide and thiosulfoxide. To shift the equilibrium to favor the ligation, placement of substituents at R 1 is obligatory for alkyl allyl disulfides. Nonetheless, alkyl buta-2,3-dienyl disulfides may also undergo the ligation at room temperature without the help of the R 1 substituent.
Li
Zhe
Z
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
Wang
Chen
C
Fu
Yao
Y
Guo
Qing-Xiang
QX
Liu
Lei
L
D000498:Allyl Compounds / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013454:Sulfoxides / Q000737:chemistry; D013816:Thermodynamics
D000498:Allyl Compounds; D004220:Disulfides; D009943:Organophosphorus Compounds; D013438:Sulfhydryl Compounds; D013454:Sulfoxides; C061896:triphenylphosphine; C028009:diallyl disulfide