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What is the mechanism of amine conjugate additions to pyrazole crotonate catalyzed by thiourea catalysts?
Abstract
Aminoindanol-derived thioureas catalyze proton transfer and do not stabilise anions in an asymmetric conjugate addition to pyrazole crotonate. Calculations show that the urea H-bonds play different roles in the preferred transition state and in the one leading to the minor enantiomer in the mechanism of hydroxy-thiourea catalyzed conjugate additions to pyrazole crotonates.
The isothiourea-catalyzed formal enantioselective conjugate addition of 2-hydroxybenzophenone imine derivatives to α,β-unsaturated para-nitrophenyl esters has been developed. Investigations of the scope and limitations of this procedure showed that β-electron withdrawing substituents within the α,β-unsaturated ester component was necessary for good product yield, giving rise to a range of β-imino ester and amide derivatives in moderate to good isolated yields with excellent enantioselectivity (20 examples, up to 81% yield and 97:3 er).
The reaction mechanism and regioselectivity for the gold(I)-catalyzed hydroamination reaction of terminal alkenes are analyzed by means of density functional theory (DFT) calculations. The influence of the nature of the olefin as well as the ligand present in the gold(I) catalyst on the regioselectivity is investigated. The anti-Markovnikov addition is preferred for some alkenes, particularly those having cyclopropyl or good electron-withdrawing groups in their structures. The regioselectivity of the process is quantitatively analyzed with the help of state-of-the-art computational methods, namely, the activation strain model (ASM) of reactivity and natural orbitals for chemical valence (NOCV) method. It is found that the back-bonding interactions in the initially formed π-complex are directly related to the Gibbs energy barrier difference between the Markonikov and anti-Markovnikov additions. It can be concluded that the coordination mode of the initial π-complex ultimately controls the regioselectivity outcome of the transformation.
The acetylacetone-benzaldimine Mannich reaction catalysed by Mg(II) and Ca(II) salts of chiral phosphoric acids (CPA) has been investigated computationally by QM/MM methods. Enantioselectivity in this reaction is both larger, and in the opposite sense to that observed for the same reaction catalysed by the protic CPA catalyst alone. We present a mechanistic model from which the characteristic differences between these metal and metal-free catalysts, which can co-exist in the same reaction mix-ture, can be understood. Alkaline earth salts with chiral phosphate counterions are found to be more catalytically active than the protic form, and the Ca(II) and Mg(II) CPA salts react via different mechanisms, with a higher coordination number fa-vored by calcium over magnesium. In the well-ordered chiral cavities around these metal centers, asymmetric induction arises from the steric interaction with the imine protecting group in the unfavourable pathway, with both substrates adopting well-defined conformations. These mechanistic models have allowed us to rationalize the stereochemical outcome across a range of bimolecular reactions promoted by divalent metal phosphates formed with different CPAs.
A very useful outcome of theoretical investigations of organocatalytic reaction mechanism are qualitative reaction models or predicting guides, that allows forecasting the degree and sense of the enantioselectivity of the reaction involving novel sustrates. However, application of these models can be unexpectedly challenging in reactions affected by large number of conformations and potential control of the enantioselectivity by different reaction steps. The QM/MM study of the Friedel-Crafts reaction between indole and the N-tosylimide of benzaldehyde catalysed by different CPA reveals that the reaction consists in two CPA-assisted steps: the addition of the two reagents to yield a Wheland intermediate, and its re-aromatization. The relevance of the second step depends on the catalyst: it changes the sense of the expected stereoselectivity for a BINOP derived CPA, but is irrelevant in the reaction catalysed by a VAPOL derived imidodiphosphoric acid catalyst. Although the relative energies of the TSs can be rationalized considering the steric interactions with the catalyst, the possibility of additional H-bonds, or the relative stability of the conformation of the reagents, predicting the enantioselectivity is not possible by qualitative guides.
An ONIOM QM/MM study on the mechanism of the Michael addition to triple bonds catalyzed by chiral diiminophosphorane catalysts has been performed to understand the stereoselectivity of the product olefin. Our results are consistent with the experimental enantioselectivity, but more importantly, reveal that the Z vs E preference depends on the influence of the catalyst upon the geometry of the allenyl enolate formed in the addition step. These intermediates show an innate preference for a (Z)-configuration, although this can be surpressed by steric interactions due to a catalyst. This leads to two distinct mechanisms in which the kinetic basis for (E) or (Z)-stereoselectivity is determined by a different step. Bifunctional iminophosphorane catalysts are found to use steric interactions to override innate stereoelectronic effects of the allenyl enolate reactive intermediate.
The mechanism of NHC catalysed annulation reactions involving an α,β-unsaturated acyl azolium and β-naphthol has been studied using DFT methods at the MPWB1K/6-311G(d,p) level in toluene. For the C-C bond formation step, which corresponds to the rate- and stereo-determining step of this NHC catalysed reaction, the two competitive addition modes, i.e. the 1,2- and the 1,4-additions, have been studied. In toluene, acyl azolium forms an ion pair (IP) with the counterion chloride anion. Interestingly, β-naphthol forms a hydrogen bond with the chloride anion of IP, increasing the nucleophilic character of β-naphthol and the electrophilic character of the acyl azolium moiety. For the first time, the transition state (TS) associated with the 1,2-addition is found and characterised. An analysis of the activation Gibbs free energies involved in the two competitive pathways makes it possible to rule out the pathway associated with the 1,2-addition. The relative Gibbs free energy of stereoisomeric TSs present in the 1,4-additions, accounts for the experimentally observed stereoselectivity. Finally, a comparative study of the pathways associated with the 1,2- and the 1,4-addition of β-naphthalenethiol to the acyl azolium moiety of IP accounts for the low reactivity of β-naphthalenethiol in these NHC catalysed annulation reactions involving α,β-unsaturated acyl azoliums.
Two characteristics are required for a reagent to be a useful partner in a chiral reaction, it must be able to bind to the catalyst to generate a reacting intermediate with a well-defined enantioface discrimination, and it must have substituents suitable for further modifications of the reaction products. N-Acyliden penta-atomic aza-heterocycles fulfill these conditions, they have the carbonyl group suitable for the coordination to the catalyst, and the leaving character of the heterocycle bound to the carbonyl group allows the conversion of the products into a variety of functionalized chiral building blocks. If the heterocycle has a further point of coordination to the catalyst, the reagent may behave as a bidentate ligand, making the reaction easier and the chiral product more stereoselective, as discussed for many reactions in the previous sections. The products of the enantioselective reactions are often useful intermediates for the syntheses of natural or biologically active compounds.
The synthesis of antimicrobial beta-nitrohydrazides, as the target product of our reaction, is reached for the first time under organocatalytic enantioselective conditions. We accomplish this goal by using a thiourea organocatalysed aza-Michael addition reaction of hydrazide to nitroalkenes, furnishing final products with good yields and good enantiomeric ratios. The developed methodology is one of the rare examples of catalytic reactivity using hydrazide where the reaction proceeds through its N-2 atom. Our developed strategy extends the generality of this area of research due to the difficulties of designing new nitrogen nucleophiles with high activity, and in addition, this is one of the scarce examples where nitroalkenes and chiral thioureas have been used in asymmetric organocatalytic aza-Michael addition reactions.
The scientific review introduces the details of the original ONIOM method developed by the Morokuma group, while discussing and comparing latest improvements of the ONIOM method and alternative approaches. It presents an overview of the applications of the ONIOM method to seven important chemical, biological, and material systems, such as organic systems, inorganic compounds and homogeneous catalysis, heterogeneous catalysis, nanomaterials, excited states, solution chemistry, and biological macromolecules. The scientific review discusses the methods originally developed by Morokuma and coworkers to clearly present the original ideas and concepts of the IMOMM, IMOMO, and ONIOM methods.
We present a method for evaluating second-order Moller−Plesset (MP2) energy and gradients for solvated molecules described within the polarizable continuum model (PCM). The explicit inclusion of solvent effects into the evaluation of the relaxed MP2 density through the Z-vector technique is reported and analyzed. Applications to some one-electron response properties (dipoles, electrostatic molecular potentials, electric field gradients) as well as nuclear gradients are presented.
A contracted Gaussian basis set (6‐311G∗∗) is developed by optimizing exponents and coefficients at the Møller–Plesset (MP) second‐order level for the ground states of first‐row atoms. This has a triple split in the valence s and p shells together with a single set of uncontracted polarization functions on each atom. The basis is tested by computing structures and energies for some simple molecules at various levels of MP theory and comparing with experiment.
A new procedure, QRC calculation, is presented which provides useful information for analysing organic reactions and links transition structures to starting materials and products. QRC calculations are an alternative to computationally demanding IRC calculations, which find more information than is needed for this analysis.
The molecular mechanisms for nucleophilic addition of an ammonia molecule to three small molecules with activated double bonds-acrolein (ACR), acrylonitrile (ACN), and acrylic acid (AA)-have been examined with ab initio quantum chemical methods in reactions modeling their interactions with biological targets. The calculations include the nucleophilic addition reaction of either an ammonia molecule or an NH3 hydrogen bonded to a discrete water molecule (NH3.OH2) to ACR, ACN, and AA. Optimizations of the geometries of reactants and transition structures for the 1,2- and 1,4-addition mechanisms were done at the restricted Hartree-Fock level with 6-31G basis sets, and electron correlation energy was calculated at the MP2 level with 6-31G* basis sets. Reaction energies were corrected for zero-point energies calculated from the harmonic vibrational frequencies of the 6-31G optimized structures. Hydration enthalpies were evaluated with the solvent described as a polarizable dielectric continuum. The barriers calculated for the addition reactions were found to be significantly reduced by the assistance of a solvent molecule in the intramolecular proton-transfer process. The order of reactivities, based on energies of activation of the 1,4-addition to ACR, either 1,2- or 1,4-addition to AA, and 1,2-addition to ACN, is as follows: ACR > AA > ACN, in very good agreement with experimental results. The results provide inferences regarding the relative capabilities of the molecules in this class to interact with DNA and reflect on their relative potencies in reactions determining the biological effects of these environmentally important chemical species.
Highly enantioselective addition reactions between silyl ketene acetals and N-Boc aldimines are catalyzed by the thiourea-based catalyst 1c. Extraordinary scope is observed in this methodology with regard to the imine substrate, with aryl and heteroaromatic derivatives generally affording nearly quantitative yields of β-amino ester product in up to 98% enantioselectivity.
An approximate method, recently proposed to include in continuum solvation models the effects of electronic charge lying outside the solute cavity, has been adapted and implemented in the framework of the polarizable continuum model (PCM). This formulation exploits all the features already developed for the other PCM versions; it provides molecular free energies, gradients and second derivatives with respect to nuclear coordinates. The performances of this method have been tested in comparison with other PCM versions, in particular, we examined the reliability of this technique to reproduce actual volume charge distribution effects, compared to traditional procedures based on Gauss’ Law. © 2001 American Institute of Physics.
The integrated MO+MO (IMOMO) method, recently proposed for geometry optimization, is tested for accurate single point calculations. The principle idea of the IMOMO method is to reproduce results of a high level MO calculation for a large ‘‘real’’ system by dividing it into a small ‘‘model’’ system and the rest and applying different levels of MO theory for the two parts. Test examples are the activation barrier of the SN2 reaction of Cl−+alkyl chlorides, the C=C double bond dissociation of olefins and the energy of reaction for epoxidation of benzene. The effects of basis set and method in the lower level calculation as well as the effects of the choice of model system are investigated in detail. The IMOMO method gives an approximation to the high level MO energetics on the real system, in most cases with very small errors, with a small additional cost over the low level calculation. For instance, when the MP2 (Møller–Plesset second‐order perturbation) method is used as the lower level method, the IMOMO method reproduces the results of very high level MO method within 2 kcal/mol, with less than 50% of additional computer time, for the first two test examples. When the HF (Hartree–Fock) method is used as the lower level method, it is less accurate and depends more on the choice of model system, though the improvement over the HF energy is still very significant. Thus the IMOMO single point calculation provides a method for obtaining reliable local energetics such as bond energies and activation barriers for a large molecular system. © 1996 American Institute of Physics.
The polarizable continuum model (PCM), used for the calculation of molecular energies, structures, and properties in liquid solution has been deeply revised, in order to extend its range of applications and to improve its accuracy. The main changes effect the definition of solute cavities, of solvation charges and of the PCM operator added to the molecular Hamiltonian, as well as the calculation of energy gradients, to be used in geometry optimizations. The procedure can be equally applied to quantum mechanical and to classical calculations; as shown also with a number of numerical tests, this PCM formulation is very efficient and reliable. It can also be applied to very large solutes, since all the bottlenecks have been eliminated to obtain a procedure whose time and memory requirements scale linearly with solute size. The present procedure can be used to compute solvent effects at a number of different levels of theory on almost all the chemical systems which can be studied in vacuo. © 2002 American Institute of Physics.
A set of rules for determining the atomic radii of spheres used to build the molecular cavities in continuum solvation models are presented. The procedure is applied to compute the hydration free energy for molecules containing H, C, N, O, F, P, S, Cl, Br, and I at a computational level (Hartree–Fock with a medium size basis set) allowing the study of relatively large systems. The optimized radii reduce the mean error with respect to the experimental solvation energies below 0.20 kcal/mol for a set of 43 neutral solutes and around 1 kcal/mol for 27 ions. Moreover the correct trends are observed for the solvation energies of homolog series, like the series ammonia–trimethylamine, that are not correctly reproduced by usual solvation models. © 1997 American Institute of Physics.
a][] Francisco M. Muñiz, [a] Silvia Sáez, [a] César Raposo, [b] and Joaquín R. Morán [a] Keywords: Homogeneous catalysis / Supramolecular chemistry / Hydrogen bonds / Reaction mechanisms / Molecular modelling Different artificial enzymes, based on the theozyme concept, have been designed for Michael additions of pyrrolidine to α,β-unsaturated lactams. These molecules each have skel-eton able to mimic a structure called an "oxyanion hole", as is present in many enzymes. Amine groups are also responsi-ble for the catalytic activities of these receptors, since they support the important proton-transport step. The require-ment for the amine groups was established from the reaction