Modeling the mechanism of ester-substituted alkynes in acyloxy migration followed by various cycloaddition reactions

In the present thesis quantum chemical methods have been used to model the mechanism of Rh-catalyzed acyloxy migrations followed by cycloaddition reactions of propargyl esters. The necessary background information and the literature are introduced in Chapter 1. The theoretical framework of quantum chemistry is presented in Chapter 2. The results of the thesis are discussed in Chapter 3 and Chapter 4. Finally, the main conclusions are summarized in Chapter 5. One of the main targets of synthetic chemistry is an effective production of desired compounds. In this respect, metal catalyzed reactions have contributed to this area by enabling many synthetic utilities including regioselective or stereoselective synthesis. However, in most of these cases, the mechanism of the metal catalyzed reactions are recondite. At this point, mechanistic studies, especially quantum mechanical modelling of reactions are very valuable as they exhibit wide range of information on the dynamics of a reaction, including the structural factors that affect product distribution, transition state structures, ligand effect, metal's contibution to mechanism. The main aim of this study is to investigate the reaction mechanisms for the formation of functionalized cyclohexenone and cyclopentenone derivatives via tandem acyloxy migration and cycloaddition via Rh catalyst. This thesis consists of two parts of work. In the first part, the two competitive 1,2- and 1,3-acyloxy migrations have been discussed and the effect of the nature of alkynes, terminal vs internal, in regioselectivity has been investigated by considering [4+1] and [5+1] cycloadditions of 3-acyloxy 1,4-enynes (ACEs) with terminal and internal alkynes. In the second part, the mechanism of a tandem 1,3-acyloxy migration [5+1] cycloaddition of cyclopropyl substituted propargyl esters has been investigated. The effect of the substituent in the cyclopropane has been studied to elucidate the mechanism of cyclopropyl ring opening which leads to product distribution. In the first part of the thesis, the mechanisms of the [RhCl(CO)2]2-catalyzed intramolecular cycloadditions of ACEs with a cyclohexene moiety by CO with concominant acyloxy (OAc) migrations have been extensively investigated using density functional theory (DFT) calculations. All geometries were optimized at the B3LYP/6-31+G(d) level (LANL2DZ for Rh). The effect of the nature of alkynes has been rationalized by modelling possible intermediates and transition states for competitive 1,2- vs 1,3-migrations of acyloxy group and for further possible transformations with terminal and methyl substituted starting enynes. Experimental and mechanistic studies indicate that the formation of cyclohexadienones proceeded by a [5+1] type cycloaddition of ACEs with terminal alkynes involving a Rautenstrauch 1,2-OAc migration by carbonylation while the formation reaction of functionalized cyclopentenones involved a Saucy-Marbet 1,3-OAc migration of ACEs of substituted alkynes and subsequent [4 + 1] cycloaddition with CO. The reaction initiates with two isomers of ACE-RhCl(CO) π-complex by switching the positions of CO and Cl ligands. The isomer in which CO is trans to the alkyl group has been found to be more stable because Rh metal coordinates to both alkyne and alkene fragments strongly. The acyloxy migration is found to be the rate determining step from the DFT study and the predicted regioselectivity is in harmony with the experimental result. The ~5 kcal/mol of Gibbs free energy difference between 1,2 and 1,3-acyloxy migration transition states favor 1,2-acyloxy migration for terminal or H-substituted alkynes which is consistent with the experimental and theoretical findings. The Rh-allyl complex, can undergo CO insertion with two possible reaction pathways. In the first path, CO addition to rhodium in Rh-allyl complex and then CO insertion to the cycle take place. In the second path, isomerization takes place before CO addition which leads to a more stable isomer. The following CO insertion steps prove that the isomerized intermediate is energetically favored through the reaction mechanism. On the other hand, the insertion of carbonyl group from cyclohexane side is found to be favored compared to the alkene side which leads to the ketene formation when Rh is expelled from the system by complexing to another ACE. The rhodacycloheptadienone which is obtained through CO insertion from cyclohexane side undergoes reductive elimination. The cyclohexadienone product is obtained when the catalyst leaves the system by coordinating with another ACE molecule and the starting Rh-ACE complex is regenerated. In internal alkynes, the preference of 1,3- is not strong as compared to 1,2-acyloxy migration, therefore, both mechanisms were modeled. The barrier heights for the following steps of 1,2-migration are found to be higher than that of 1,3-acyloxy migration. Furthermore, a probable equilibrium between Rh-allyl complex and Rh-ACE complex indicates that 1,2-acyloxy migration is a less facile path for internal alkynes. Additionally, 1,3-acyloxy migration intermediate called Rh-allenyl complex is also experimentally proposed. As it is discussed in the terminal part, calculations have shown that the isomerization step is energetically preferable compared to a direct CO addition and CO insertion from the cyclohexane side is energetically favored. The resulting rhodacyclohexenone undergoes reductive elimination and the catalyst leaves the system by coordinating with another ACE. The calculations presented herein have contributed to understanding and thus will lead to controlling this effective Rh (I) catalyzed transformation reactions of 1,2 and 1,3-acyloxy migration followed by cycloaddition for further cyclohexadienone and cyclopentenone derivatives in obtaining custom made products. In the second part of the thesis, the carbonylation mechanism of cyclopropyl substituted propargyl esters has been modeled with DFT at WB97XD/6-31+G(d) level (LANL2DZ for Rh). Although B3LYP functional was used in the fist part of the thesis, it was not succesful enough to investigate 1,3-acyloxy migration of cyclopropyl substituted propargyl esters in solution. On the other hand, a long range WB97XD functional is found to be good at highlighting the acyloxy migration. The cleavage of different cyclopropane C-C σ-bonds led to different isomers for the unsymmetrically substituted cyclopropanes. The regioselectivity for the cleavage of C-C σ-bonds is found to be dependent on the stereochemistry of the cyclopropyl group, the metal catalysts and the electronic properties of the substituents. In this thesis, cis and trans conformers of 3-(2-Hydroxymethyl-cyclopropyl)-1,1-dimethyl-prop-2-ynyl ester and trans conformer of 3-(2-Phenyl-cyclopropyl)-1,1-dimethyl-prop-2-ynyl ester have been modeled to highlight the reaction mechanism and explain the product distribution. Although both trans- and cis-disubstituted cyclopropanes with hydroxymethyl moiety prefer the cleavage of the less hindered C-C σ-bond of cyclopropane, a higher regioselectivity is observed in cis-substituted cyclopropane than the corresponding trans-counterpart. Moreover, trans conformers with hydroxymethyl and phenyl substituted cyclopropanes have opposite regioselectivities. 1,3-acyloxy migration of cyclopropyl substituted propargyl esters is a step-wise process which takes place in the first two transition states. The formed Rh-allenyl complex undergoes isomerization, CO addition and then ring opening. The resulting metallacycle undergoes CO insertion followed by reductive elimination. In the last step, alkylidene cyclohexenone product forms when the catalyst leaves the system by coordinating with another ACE. The energies of the intermediates formed by direct CO addition or isomerization followed by CO addition have been compared. As in the first part of the thesis, the resulting isomer is exothermically preferred. Isomerization leads to a lower energy transition state and an intermediate for the following CO insertion. Furthermore, CO insertion has been investigated in terms of the positions of carbonyl group to the cleavaged C-C σ-bond of cyclopropane. The calculations herein show that the initial reactant energies and the barrier heights for CO insertion have a large effect on product distribution for trans and cis conformers. The 4.9 kcal/mol of energy difference in CO insertions of trans-disubstituted cyclopropanes favors the cleavage of the least substituted C-C σ-bond, leading to the major product. While the high selectivity of the least substituted C-C σ-bond in cis conformers have been explained by 3 kcal/mol of energy difference in the initial complexes and 4.9 kcal/mol of energy difference in CO insertions. The opposite selectivity of trans-disubstituted cyclopropanes with phenyl group in which the most substituted C-C σ-bond is cleaved for ring expansion is due to the electronic effect of the adjacent π-system. Finally, the results in this study are consistent with the experimental findings. As a part of this thesis, a poster has been presented in an international symposium and a paper has been published in a SCI indexed peer-reviewed journal (10.1016/j.jorganchem.2017.09.017).