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Ab initio and density functional theory methods are used for studying the photonucleophilic aromatic substitution reactions of nitrobenzene derivatives. The preference seen for the meta or para pathways in the addition step is predicted by using the spin-polarized Fukui functions applied for the prereactive [pi]-complex.

The regioselectivity of ring-forming radical reactions is investigated within the framework of the so-called spin-polarized conceptual density functional theory. Two different types of cyclizations were studied. First, a series of model reactions of alkyl- and acyl-substituted radicals were investigated. Next, attention was focused on the radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals (a three-step mechanism). In both of these reactions, the approaching radical (carbon or nitrogen centered) adds to a carbon—carbon double bond within the same molecule to form a radical ring compound. In this process, the number of electrons is changing from a local point of view (a charge transfer occurs from one part of the molecule to another one) at constant global spin number Ns (both the reactant and the product ring compound are in the doublet state). It is shown that the experimentally observed regioselectivities for these ring-closure steps can be predicted using the spin-polarized Fukui functions for radical attack, ƒNN0(r). [ABSTRACT FROM AUTHOR]

Anti-Felkin-Anh diastereoselectivity can be achieved for nucleophilic additions to α-chiral ketones upon stretching the ketone with a mechanical pulling force. Herein, a mechanochemical Felkin-Anh model is proposed for predicting the outcome of a nucleophilic addition to an α-chiral ketone. Essentially, the fully stretched chiral ketone has one substituent shielding each side of the carbonyl, in contrast to the Felkin-Anh model, in which free rotation around a bond is required to achieve the two rotamers of the ketone. Depending on the pulling scenario, either Felkin-Anh or anti-Felkin-Anh diastereoselectivity is obtained. The model is entirely based on the distance between the pulling points, which is maximized in the anti-periplanar arrangement. The major diastereomer is associated with the approach with the least steric interactions. The intuitive model is validated by means of mechanochemical density functional theory calculations. Importantly, the ketone is fully stretched in the sub 1 nN force regime, thus minimizing the risk of undesired homolytic bond rupture. Moreover, the mechanical force is not used for lowering the reaction barriers associated with the nucleophilic addition; instead, it is solely applied for locking the conformation of a molecule and provoking otherwise inaccessible reaction pathways on the force-modified potential energy surface.

The conjugated π-system in polyenes can be interrupted by electrocyclic ring-closure reactions. In this work, this 6π-electrocylization is shown by means of density functional calculations to be reversible by the application of an external mechanical pulling force at the terminal ends of the interrupted polyene chain. The test systems were constrained in a fused ring system, thus locking the orientation of three π-bonds and generally promoting 6π-electrocyclic ring-closure reactions. For several systems, the forward reaction is exergonic and the corresponding reaction barrier is comparable to those reported in the literature. The reverse reaction is triggered by an external pulling force of 2 nN (nano-Newton) or less and also becomes exergonic in all investigated polyenes under these force conditions. Moreover, it proceeds via a low reaction barrier when a pulling force of 2 nN is active, indicating that the mechanical force is an efficient stimulus for triggering ring-opening reactions. Analysis of the strain energy induced by this mechanical force confirms an optimal activation of the corresponding C-C σ-bond that breaks upon ring opening when the pulling positions are located on the polyene chain.

A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared exo -methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides. The reactivity of this constrained building block was evaluated and compared to the corresponding 4'-spirocyclic furanose analogues. Density functional theory calculations were performed to support the observed selectivity in the carbonyl reduction of spirocyclobutanone building blocks. Starting from novel spirocyclic intermediates, we exemplified the preparation of an undescribed class of carbocyclic nucleoside analogues and provided a proof of concept for application as inhibitors for the protein methyltransferase target PRMT5.

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of cis alcohol (>90%), irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing the solvent polarity. On the computational side, density functional theory and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the antifacial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interactions in the case of a syn-facial hydride attack. The computed cis/trans ratios are in good agreement with the experimental ones and thus show the potential of computational chemistry for predicting and rationalizing the stereoselectivity of hydride reductions of cyclobutanones.

The role of the solvent and the influence of dynamics on the kinetics and mechanism of the SNAr reaction of several halonitrobenzenes in liquid ammonia, using both static calculations and dynamic ab initio molecular dynamics simulations, are investigated. A combination of metadynamics and committor analysis methods reveals how this reaction can change from a concerted, one-step mechanism in gas phase to a stepwise pathway, involving a metastable Meisenheimer complex, in liquid ammonia. This clearly establishes, among others, the important role of the solvent and highlights the fact that accurately treating solvation is of crucial importance to correctly unravel the reaction mechanism. It is indeed shown that H-bond formation of the reacting NH3 with the solvent drastically reduces the barrier of NH3 addition. The halide elimination step, however, is greatly facilitated by proton transfer from the reacting NH3 to the solvent. Furthermore, the free energy surface strongly depends on the halide substituent and the number of electron-withdrawing nitro substituents.

meso-Substituted pentaphyrins(1.1.1.1.1) were unexpectedly isolated as N-fused species under Rothemund-type conditions. The reaction mechanism is unknown at present, but the first example of a nonfused [22]pentaphyrin was reported in 2012. Here, the conformational preferences and N-fusion reaction of [22]- and [24]pentaphyrins have been investigated using density functional calculations, together with their aromaticity-molecular topology relationships. Two global minima are found for the unsubstituted [22]pentaphyrin corresponding to T0 and T0(4,D) Hückel structures. Möbius transition states are located in the interconversion pathways with activation barriers of 27 kcal mol(-1). Conversely, [24]pentaphyrin is able to switch between Hückel and Möbius conformers with very low activation barriers. However, nonfused [24]pentaphyrins are unstable and spontaneously undergo an N-fusion reaction driven by the strain release. On the contrary, nonfused [22]pentaphyrins could be isolated if a T0(4,D) conformation is adopted. Importantly, conformational control of pentaphyrins can be achieved by meso-substituents. Two stable conformations (T0(4,D) and T0(A,D)) are found for the nonfused [22]pentaphyrin, which are delicately balanced by the number of substituents. The T0(A,D) conformation is preferred by fully meso-aryl pentaphyrins, which is converted to the N-fused species. Interestingly, the removal of one aryl group prevents the N-fusion reaction, providing stable aromatic nonfused [22]pentaphyrins in excellent agreement with the experimental results.

In this study, for the first time inverse design was applied to search for the intrinsically most stable radical system in a predefined chemical space of enormous size by scanning in a rational way that entire chemical space. The focus was predominantly on thermodynamic stabilization effects, such as stabilization through resonance. Two different properties were optimized: a newly introduced descriptor called the radical delocalization value and the intrinsic stability via a previously established bond dissociation enthalpy model. The thiadiazinyl radical was chosen as case study of this new approach of inverse design in stable radical chemistry. The resulting optimal structure is found to be highly stable, intrinsically more so than other well-known stable radicals, such as verdazyls and N,N-diphenyl-N'-picrylhydrazyl, and even rivaling the intrinsic stability of nitrogen monoxide.

The photocycloaddition reaction of benzene with ethylene has been studied at the CASSCF level, including the characterization of an extended conical intersection seam. We show that the chemical selectivity is, in part, controlled by this extended conical intersection seam and that the shape of the conical intersection seam can be understood in terms of simple VB arguments. Further, the shape and energetics of the asynchronous segment of the conical intersection seam suggest that 1,2 (ortho) and 1,3 (meta) will be the preferred chemical products with similar weight. The 1,4 (para) point on the conical intersection is higher in energy and corresponds to a local maximum on the seam. VB analysis shows that the pairs of VB structures along this asynchronous seam are the same and thus the shape will be determined mainly by steric effects. Synchronous structures on the seam are higher in energy and belong to a different branch of the seam separated by a saddle point on the seam. On S1 we have documented three mechanistic pathways corresponding to transition states (with low barriers) between the reactants and the conical intersection seam: a mixed asynchronous/synchronous [1,2] ortho path, an asynchronous [1,3] meta path, and a synchronous [1,3] meta path.

The difference in reactivity between the activated 2-bromomethyl-1-tosylaziridine and the nonactivated 1-benzyl-2-(bromomethyl)aziridine with respect to sodium methoxide was analyzed by means of DFT calculations within the supermolecule approach, taking into account explicit solvent molecules. In addition, the reactivity of epibromohydrin with regard to sodium methoxide was assessed as well. The barriers for direct displacement of bromide by methoxide in methanol are comparable for all three heterocyclic species under study. However, ring opening was found to be only feasible for the epoxide and the activated aziridine, and not for the nonactivated aziridine. According to these computational analyses, the synthesis of chiral 2-substituted 1-tosylaziridines can take place with inversion (through ring opening/ring closure) or retention (through direct bromide displacement) of configuration upon treatment of the corresponding 2-(bromomethyl)aziridines with 1 equiv of a nucleophile, whereas chiral 2-substituted 1-benzylaziridines are selectively obtained with retention of configuration (via direct bromide displacement). Furthermore, the computational results showed that explicit accounting for solvent molecules is required to describe the free energy profile correctly. To verify the computational findings experimentally, chiral 1-benzyl-2-(bromomethyl)aziridines and 2-bromomethyl-1-tosylaziridines were treated with sodium methoxide in methanol. The presented work concerning the reactivity of 2-bromomethyl-1-tosylaziridine stands in contrast to the behavior of the corresponding 1-tosyl-2-(tosyloxymethyl)aziridine with respect to nucleophiles, which undergoes a clean ring-opening/ring-closure process with inversion of configuration at the asymmetric aziridine carbon atom.

C-H(ax)···Y(ax) contacts are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts is investigated in this work. MP2/6-31+G(d,p) calculations predicted the presence of improper hydrogen bonded C-H(ax)···Y(ax) contacts of different strength in substituted cyclohexane rings. To support the theoretical predictions with experimental evidence, several synthetic 2-substituted adamantane analogues (1-24) with suitable improper H-bonded C-H(ax)···Y(ax) contacts of different strength were used as models of a substituted cyclohexane ring. The (1)H NMR signal separation, Δδ(γ-CH(2)), within the cyclohexane ring γ-CH(2)s is raised when the MP2/6-31+G(d,p) calculated parameters, reflecting the strength of the H-bonded C-H(ax)···Y(ax) contact, are increased. In molecules with enhanced improper H-bonded contacts C-H(ax)···Y(ax), like those having sterically crowded contacts (Y(ax) = t-Bu) or contacts including considerable electrostatic attractions (Y(ax) = O-C or O═C) the calculated DFT steric energies of the γ-axial hydrogens are considerably reduced reflecting their electron cloud compression. The results suggest that the proton H(ax) electron cloud compression, caused by the C-H(ax)···Y(ax) contacts, and the resulting increase in Δδ(γ-CH(2)) value can be effected not just from van der Waals spheres compression, but more generally from electrostatic attraction forces and van der Waals repulsion, both of which are improper H-bonding components.

Radical additions to substituted alkenes are among the most important reactions in radical chemistry. Nonetheless, there is still some controversy in the literature about the factors that affect the rate and regioselectivity in these addition reactions. In this paper, the orientation of (nucleophilic) radical additions to electron-rich, -neutral, and -poor monosubstituted substrates (11 reactions in total) is investigated through the use of chemical concepts and reactivity descriptors. The regioselectivity of the addition of nucleophilic radicals on electron-rich and -neutral alkenes is thermodynamically controlled. An excellent correlation of 94% is found between the differences in activation barriers and in product stabilities (unsubstituted versus substituted site attack). Polar effects at the initial stage of the reaction play a significant role when electron-poor substrates are considered, lowering the extent of regioselectivity toward the unsubstituted sites, as predicted from the stability differences. This is nicely confirmed through an analysis for each of the 11 reactions using the spin-polarized dual descriptor, matching electrophilic and nucleophilic regions.

Bond dissociation enthalpies (BDEs) of a large series of molecules of the type A-B, where a series of radicals A ranging from strongly electrophilic to strongly nucleophilic are coupled with a series of 8 radicals (CH2OH, CH3, NF2, H, OCH3, OH, SH, and F) also ranging from electrophilic to nucleophilic, are computed and analyzed using chemical concepts emerging from density functional theory, more specifically the electrophilicities of the individual radical fragments A and B. It is shown that, when introducing the concept of relative radical electrophilicity, an (approximately) intrinsic radical stability scale can be developed, which is in good agreement with previously proposed stability scales. For 47 radicals, the intrinsic stability was estimated from computed BDEs of their combinations with the strongly nucleophilic hydroxymethyl radical, the neutral hydrogen atom, and the strongly electrophilic fluorine atom. Finally, the introduction of an extra term containing enhanced Pauling electronegativities in the model improves the agreement between the computed BDEs and the ones estimated from the model, resulting in a mean absolute deviation of 16.4 kJ mol(-1). This final model was also tested against 82 experimental values. In this case, a mean absolute deviation of 15.3 kJ mol(-1) was found. The obtained sequences for the radical stabilities are rationalized using computed spin densities for the radical systems.

The [2 + 1] cycloadditions of carbon monoxide and carbon monothioxide CX (X = O, S) to acetylenes (R1C triple bond CR2 with R1 = H, OH and R2 = CH3, OH, NH2, C6H5) have been studied at the B3LYP/6-311G(d,p) level. It has been shown that the reaction proceeds in two steps forming first an intermediate having the properties of both a carbene and a zwitterion followed by a ring closure leading to cyclopropenones or cyclopropenethiones. The solvent effect does not play an important role in the course of the cycloaddition. The estimation of the first vertical excitation energies by CIS and TD-B3LYP methods shows that the reactions likely take place in the ground state rather than in an excited state. All the studied cyclopropenones and cyclopropenethiones are aromatic as shown by their NICS values and confirmed by calculated and experimental NMR chemical shifts. Different reactivity criteria including HOMO coefficient, local softness, hardness, polarizability, and NICS are used to predict the site selectivity in all studied cases, and the NICS criterion seems to yield the best results among them.

The Diels-Alder reactions of various quinodimethanes with ethylene are studied by means of ab initio molecular orbital and density functional theory (DFT) to show the effect of aromaticity on the reaction path. The calculations reveal that these reactions are both kinetically and thermodynamically much more favored than the prototype butadiene-ethylene Diels-Alder reaction due to the aromatization process in the transition state (TS) and product. A progressive aromaticity gain is noticed during the reaction, and hence the partial pi-delocalized peripheral diene ring function is coupled with the six-electron sigma,pi-delocalized cyclic unit resulting in an enhanced aromaticity of the TS. The magnetic criteria such as magnetic susceptibility exaltation and nucleus independent chemical shift provide definitive evidence for and fully support the aromatization process and the aromaticity of the TS. The extent of sigma-pi delocalization and the bond make-break at the TS are consistent with each other, and this is strongly influenced by the adjacent pi-aromatization process. Moreover, the aromaticity trends in the resulting TSs and products parallel the activation and reaction energies; the extent of aromatization increases with increasing reaction rate and exothermicity. This confirms that aromaticity is the driving factor governing cycloadditions involving quinodimethanes.

A theoretical study is performed of the Diels-Alder reactions of various o-quinodimethanes (QDM) with C(60) by the AM1 model and limited ab initio and DFT techniques. All reactions are shown to proceed through a concerted transition state possessing a considerable net aromaticity as evidenced from bond orders and magnetic criteria such as the magnetic susceptibility exhaltations (MSE) and nucleus independent chemical shifts (NICS) and produce different kinds of aromatic stabilized fullerene cycloadducts. Computations show that a strong LUMO-dienophile control of C(60) is realized by the influence of pyramidalization, but its high reactivity over alkene appears to be governed by the global aromaticity on fullerene rather than its strain. The aromatic functionalization occurring in QDM upon cycloaddition drastically increases the reaction rate and exothermicity of all QDM-C(60) reactions as compared to the butadiene-C(60) reaction. In fact, the simultaneously existing aromatic destabilization in fullerene indicates its opposite effect to the resonance stabilization in diene; it is thus fully restricted when the gained aromaticity is transmitted from the nucleophilic QDM to the fullerene electrophile in a push-pull manner. However, the overall aromaticity effect shown by the aromatization as well as the aromaticity of C(60) seems to accelerate these reactions at an increased rate.

The influence of basicity in a set of para-substituted phenolates on the elimination-substitution ratio obtained upon reaction with p-nitrophenethyl bromide has been studied. A correlation between experimental equilibrium data (pK(a)) and reactivity indices obtained from density functional theory (DFT) was looked for in order to show that the hard and soft acids and bases principle (HSAB) is well suited to describe the basicity properties of the para-substituted phenolates. When the basicity of para-substituted phenolates increases, their global hardness and their condensed softness at the oxygen atom increase; the negative net charge, condensed nucleophilic fukui function, and condensed nucleophilic softness of the oxygen atom increase. The proposal that the alkyl halide substrate possesses a hard beta-hydrogen atom and a soft alpha-carbon was studied for p-nitrophenethyl bromide; it turns out that the beta-hydrogen atom is soft, even softer than the carbon atom. The experimental results for the elimination-substitution ratio for p-nitrophenethyl bromide can be explained from a local-local HSAB viewpoint for the para-substituted phenolates and p-nitrophenethyl bromide and not from a global-local level viewpoint as suggested before. The results suggest that para-substituted phenolates with higher basicity (harder), less delocalized negative charge into the fragment R-C(6)H(4), and a more polarizable oxygen atom (softer) do have a lower (relative) attraction toward an alkyl carbon atom (soft) than toward a hydrogen atom (softer) from p-nitrophenethyl bromide. The beta-hydrogen and alpha-carbon atoms can be considered to act as a Lewis acid toward the para-substituted phenolate nucleophile considered as a base.