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Wei, Yin (2009): Theoretical Studies in Nucleophilic Organocatalysis. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Computational methods in quantum mechanics (QM), density functional theory (DFT) and molecular mechanics (MM), and the fast increase in computer power have opened up a new avenue for solving various vital chemical problems besides conventionally experimental measures. This thesis aims at deeper understanding of the mechanism in organocatalytic transformation and studying factors influencing the activity and selectivity of nucleophilic organocatalysts by theoretical methods. First, the concept of methyl cation affinity (MCA) is introduced and the methodology is discussed about how to calculate the MCA values accurately. The identified theoretical procedure MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) is shown to provide accurate MCA values even for large molecular system. Then, it is used to calculate the MCA values of a set of commonly used N- and P-based organocatalysts. The currently known catalytic activities of nitrogen and phosphorus bases are much more readily correlated with MCA values than with proton affinity (PA) or pKa values. Thus, the MCA can be used as a guideline for the optimization of organocatalytic transformations. Later on, we extend these studies to include affinity values towards a prochiral cation. The so-called "Mosher’s Cation" (MOSC) is used to develop a new chiral descriptor for stereoselective organocatalytic transformations. By taking the example of cinchona alkaloids the energy difference between the adducts formed by re and si face attack to Mosher’s cation (MOSCAre-si) is taken as a measure of stereoinductive potential. Other properties such as continuous symmetry measures and dipole moment are also estimated and correlated with MOSCAre-si values. In many organocatalytic transformations neutral electrophiles react with neutral nucleophiles to give zwitterionic adducts at some stage of the catalytic cycle such as in the Morita-Baylis-Hillman (MBH) reaction. A series of theoretical methods have been studied systematically in order to identify theoretical methods appropriate for the reliable description of the formation of zwitterionic adducts. Geometry optimizations at the mPW1K/6-31+G(d) level provide a reliable basis for the development of compound energy schemes for the accurate description of the formation of zwitterionic adducts between neutral nucleophiles and electrophiles. Accurate energetics can be obtained using modified G3 schemes as well as double-hybrid DFT methods such as B2K-PLYP or B2-PLYP-M2. The issues concerning the reactivities and selectivities of organocatalysts in acylation reactions are further explored. The conformational properties and the stability of acylpyridinium intermediates formed in pyridine-catalyzed acylation reactions have been studied at the SCS-MP2(FC)/6-311+G(d,p)//MP2(FC)/6-31G(d) level of theory. It has been shown that stacking interactions can play a decisive role in the stability as well as the conformational preferences of these transient intermediates. The kinetic resolution of racemic 1-(1-naphthyl)ethanol catalyzed by atropisomeric derivatives of 4-dialkylaminopyridines is used as a model system for deeper understanding the mechanism of organocatalytic transformations and the factors controlling the selectivities of catalysts. Similar to other acylation reactions, the commonly accepted nucleophilic mechanism is more favorable than the general base mechanism for reactions with isobutyric anhydride. The conformational properties of the Transition State (TS) determining the selectivities are analyzed carefully. The key TS models are identified and studied to be used for rationalization of the selectivities of catalysts, and help new catalyst design. A new highly selective catalyst is suggested. From the perspective of catalysis research, 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene, which is often used in natural product synthesis, may be used as an ideal starting point for the development of new organocatalysts due to the existence of its potentially four different active sites, based on the assumption of the comparable stability of its various tautomeric forms. Our results show that this assumption is not justified because some of the proposed tautomers are of rather low thermodynamic stability. The protonated form of the 2-aminoimidazole moiety, which is present in many synthetically used derivatives of 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene, may act as electrophiles much more comfortably and with much less thermodynamic effort.