Quantum Mechanical Assessment of Nitrosamine Potency.

Nitrosamines are in the cohort of concern (CoC) as determined by regulatory guidance. CoC compounds are considered highly potent carcinogens that need to be limited below the threshold of toxicological concern, 1.5 µg/day. Nitrosamines like NDMA and NDEA require strict control, while novel nitrosamine drug substance-related impurities (NDSRIs) may or may not be characterized as potent carcinogens. A risk assessment based on the structural features of NDSRIs is important in order to predict potency because they lack substance-specific carcinogenicity. Herein, we present a quantum mechanical (QM)-based analysis on structurally diverse sets of nitrosamines to better understand how structure influences the reactivity that could result in carcinogenicity. We describe the potency trend through activation energies corresponding to α-hydroxylation, aldehyde formation, diazonium intermediate formation, reaction with DNA base, and hydrolysis reactions, and other probable metabolic pathways associated with the carcinogenicity of nitrosamines. We evaluated activation energies for selected cases such as N-nitroso pyrrolidines, N-nitroso piperidines, N-nitroso piperazines, N-nitroso morpholines, N-nitroso thiomorpholine, N-methyl nitroso aromatic, fluorine-substituted nitrosamines, and substituted aliphatic nitrosamines. We compare these results to the recent framework of the carcinogenic potency characterization approach (CPCA) proposed by health authorities which is meant to give guidance on acceptable intakes (AI) for NDSRIs lacking substance-specific carcinogenicity data. We show examples where QM modeling and CPCA are aligned and examples where CPCA both underestimates and overestimates the AI. In cases where CPCA predicts high potency for NDSRIs, QM modeling can help better estimate an AI. Our results suggest that a combined mechanistic understanding of α-hydroxylation, aldehyde formation, hydrolysis, and reaction with DNA bases could help identify the structural features that underpin the potency of nitrosamines. We anticipate this work will be a valuable addition to the CPCA and provide a more analytical way to estimate AI for novel NDSRIs.

Isomerization of Functionalized Olefins by Using the Dinuclear Catalyst [PdI (µ-Br)(Pt Bu3 )]2 : A Mechanistic Study.

In a combined experimental and computational study, the isomerization activity of the dinuclear palladium(I) complex [PdI (µ-Br)(Pt Bu3 )]2 towards allyl arenes, esters, amides, ethers, and alcohols has been investigated. The calculated energy profiles for catalyst activation for two alternative dinuclear and mononuclear catalytic cycles, and for catalyst deactivation are in good agreement with the experimental results. Comparison of experimentally observed E/Z ratios at incomplete conversion with calculated kinetic selectivities revealed that a substantial amount of product must form via the dinuclear pathway, in which the isomerization is promoted cooperatively by two palladium centers. The dissociation barrier towards mononuclear Pd species is relatively high, and once the catalyst enters the energetically more favorable mononuclear pathway, only a low barrier has to be overcome towards irreversible deactivation.

Computational Investigation of Multifaceted Cationic Rearrangement and Stereo- and Regioselectivity in the Formation of Dysideanone's Analogues.

Mechanistic studies of regiodivergent arylations of cycloalkanols to furnish enantioenriched dysideanone's analogues are performed by employing density functional theory (DFT) calculations (B3LYP-D3(SMD)/6-311++G**//B3LYP-D3/6-31+G** level of theory). On the basis of our calculations, remote γ'-C-H arylation is preferred for unsubstituted carbinol 1, an outcome from combined factors like carbocationic stability, less steric hindrance during C-C coupling, and facile dearomatization. Meanwhile, in the presence of dimethyl substituent 1Me, regioselective γ-arylation is favored by 3.4 kcal/mol, and both findings are in agreement with the reported experimental observations. Most importantly, we concur that the barrier associated with the formation of carbocation 6 and its substituted analogues correlates with the C-H arylation outcomes. Furthermore, the ß-arylation route remains unlikely for all the reaction pathways explored in this study.

Saturated N-Heterocyclic Carbene Based Thiele's Hydrocarbon with a Tetrafluorophenylene Linker.

The synthesis of a SIPr [1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene] derived Kekulé diradicaloid with a tetrafluorophenylene spacer (3) has been described. Two synthetic routes have been reported to access 3. The cleavage of C-F bond of C6 F6 by SIPr in the presence of BF3 led to double C-F activated compound with two tetrafluoro borate counter anions (2), which upon reduction by lithium metal afforded 3. Alternatively, 3 can be directly accessed in one step by reacting SIPr with C6 F6 in presence of Mg metal. Compounds 2 and 3 were well characterized spectroscopically and by single-crystal X-ray diffraction studies. Experimental and computational studies support the cumulenic closed-shell singlet state of 3 with a singlet-triplet energy gap (ΔES-T ) of 23.7 kcal mol-1 .

Computational Exploration of Mechanistic Avenues in C-H Activation Assisted Pd-Catalyzed Carbonylative Coupling.

The detailed mechanism of the intermolecular Pd-catalyzed carbonylative coupling reaction between aryl bromides and polyfluoroarenes relying on C(sp2)-H activation was investigated using state-of-the-art computational methods (SMD-B3LYP-D3(BJ)/BS2//B3LYP-D3/BS1). The mechanism unveils the necessary and important roles of a slight excess of carbon monoxide: acting as a ligand in the active catalyst state, participating as a reactant in the carbonylation process, and accelerating the final reductive elimination event. Importantly, the desired carbonylative coupling route follows the rate-limiting C-H activation process via the concerted metalation-deprotonation pathway, which is slightly more feasible than the decarboxylative route leading to byproduct formation by 1.2 kcal/mol. The analyses of the free energies indicate that the choice of base has a significant effect on the reaction mechanism and its energetics. The Cs2CO3 base guides the reaction toward the coupling route, whereas carbonate bases such as K2CO3 and Na2CO3 switch toward an undesired decarboxylative path. However, K3PO4 significantly reduces the C-H activation barrier over the decarboxylation reaction barrier and can act as a potential alternative base. The positional influence of a methoxy substituent in bromoanisole and different substituent effects in polyfluoroarenes were also considered. Our results show that different substituents impose significant impact on the desired carbonylative product formation energetics. Considering the influence of several ligands leads to the conclusion that other phosphine and N-heterocyclic carbene, such as P nBuAd2 and IMes, can be used as an efficient alternative than the experimentally reported P tBu3 ligand exhibiting a clear preference for C-H activation (ΔΔ⧧ GLS) by 7.1 and 10.9 kcal/mol, respectively. We have also utilized the energetic span model to interpret the experimental results. Moreover, to elucidate the origin of activation barriers, energy decomposition analysis calculations were accomplished for the critical transition states populating the energy profiles.

Donor Stabilized Diatomic Gr.14 E2 (E = C-Pb) Molecule D-E2-D (D = NHC, aNHC, NNHC, NHSi, NHGe, cAAC, cAASi, cAAGe): A Theoretical Insight.

Quantum chemical calculations have been carried out to explore the detailed electronic structure and bonding scenario in various bis-donor stabilized E2 compounds (E = C-Pb). Our computational findings reveal that the thermodynamic stabilities of the E2 core gradually decrease as we move down the group. A linear D-E-E'-D framework is observed for C2 systems, while the heavier group 14 analogues possess trans-bent geometries. Consideration of few compounds as viable targets for synthesis is suggested by their corresponding calculated formation energies. In addition, the thermodynamic stabilities of C2 systems notably increase with the saturation of the donor ring framework and are even more pronounced for boron-substituted saturated NHD ligand. QTAIM calculations affirmed that the covalent nature of E-E' bonds shifts toward the donor-acceptor region as one traverses from top to bottom along group 14. The E-D and E'-D bonds in the C2 systems have covalent nature, whereas those in Si2-Pb2 systems are characterized by donor-acceptor bonds. In addition, we have computed proton affinities and vertical ionization potentials (VIPs) of these compounds. An excellent correlation was obtained between calculated VIPs and orbital energies of HOMOs. Furthermore, in the present study, we also explored the effect of bis-donors in the stabilization of heterodiatomic SiC compounds. Our calculations indicate that a typical bonding description of the SiC(D)2 compounds should be represented by a combination of a classical double bond between C-D with significant donor-acceptor interaction in Si-D, i.e., D → Si═C═D. The SiC(D)2 systems are found to be less stable than the corresponding dicarbon compounds C2(D)2, but they show significant stabilization compared to the corresponding disilicon systems Si2(D)2.

Mechanistic Exploration of the Transmetalation and Reductive Elimination Events Involving PdIV -Abnormal NHC Complexes in Suzuki-Miyaura Coupling Reactions: A DFT Study.

A comprehensive DFT (M06-L-D3(SMD)/BS2//M06-L/BS1 level) investigation has been carried out to explore in detail the mechanism of the transmetalation and reductive elimination reactions of abnormal N-heterocyclic carbene (aNHC) palladium(IV) complexes within the framework of Suzuki-Miyaura cross-coupling reactions. Emphasis was placed on the role of base and the effect of countercations on the critical transmetalation and reductive elimination events involving palladium(IV) complexes. Of the two competing roles of the base, the route involving boronate formation followed by halide exchange prevails over that of direct halide exchange for the intermediates [PdIV (aNHC)(OMe)2 Cl]- Na+ (pathway A), [PdIV (aNHC)(OMe)(Cl)2 ]- Na+ (pathway B), and [PdIV (aNHC)Cl3 ]- Na+ (pathway C) emanating from the oxidative addition reaction. The results of the calculations are in accordance with our previous theoretical findings of favorable energetics for palladium intermediates incorporating two coordinated methoxy groups. The negative role played by the countercation in the transmetalation step is mainly due to the overstabilization of the pre-transmetalation intermediate, which is in line with experimental kinetic results. The anionic complexes exhibit greater affinity for the transmetalation and reductive elimination reactions than the neutral variants.

DFT Study on C-F Bond Activation by Group 14 Dialkylamino Metalylenes: A Competition between Oxidative Additions versus Substitution Reactions.

The C-F bond activation of pentafluoropyridine (PFP) by group 14 dialkylamino metalylenes has been studied employing DFT calculations. Emphasis is placed on the group 14 central atom (M = SiII, GeII, and SnII) and substituents (-NMe2, -NiPr2, -Cl, -NH2, and -PH2) dependent switching of oxidative addition to the metathesis/substitution reaction route, using state-of-the-art theoretical methods (M062X/def2-QZVP(SMD)//M062X/def2-TZVP) to provide a systematic classification of the individual mode of reactions. Moreover, an energy decomposition analysis (EDA) is implemented to get a brief insight into the physical factors that control the activation barriers originating via the different mode of reactions, viz., oxidative addition and metathesis routes. The key finding is that the distortion of PFP is the principal guiding factor in the oxidative addition reaction, while distortions imposed on both the PFP and metalylenes are inevitable toward the origin of the metathesis reaction barrier. The preferable oxidative addition reaction over metathesis of substituted silylenes can be explained on the basis of electron concentration and the HOMO-LUMO gap between the reacting substrates. However, the dramatic switch between oxidative addition and metathesis reaction in substituted germylenes depends on both the electronic and steric nature of the substituents. Similar observations are also noted for the reactivity of substituted stannylenes.

Exploring the Oxidative-Addition Pathways of Phenyl Chloride in the Presence of PdII Abnormal N-Heterocyclic Carbene Complexes: A DFT Study.

DFT calculations were performed to elucidate the oxidative addition mechanism of the dimeric palladium(II) abnormal N-heterocyclic carbene complex 2 in the presence of phenyl chloride and NaOMe base under the framework of a Suzuki-Miyaura cross-coupling reaction. Pre-catalyst 2 undergoes facile, NaOMe-assisted dissociation, which led to monomeric palladium(II) species 5, 6, and 7, each of them independently capable of initiating oxidative addition reactions with PhCl. Thereafter, three different mechanistic routes, path a, path b, and path c, which originate from the catalytic species 5, 7, and 6, were calculated at M06-L-D3(SMD)/LANL2TZ(f)(Pd)/6-311++G**//M06-L/LANL2DZ(Pd)/6-31+G* level of theory. All studied routes suggested the rather uncommon PdII /PdIV oxidative addition mechanism to be favourable under the ambient reaction conditions. Although the Pd0 /PdII routes are generally facile, the final reductive elimination step from the catalytic complexes were energetically formidable. The PdII /PdIV activation barriers were calculated to be 11.3, 9.0, 26.7 kcal mol-1 (ΔΔ≠ GLS-D3 ) more favourable than the PdII /Pd0 reductive elimination routes for path a, path b, and path c, respectively. Out of all the studied pathways, path a was the most feasible as it comprised of a PdII /PdIV activation barrier of 24.5 kcal mol-1 (ΔGLS-D3 ). To further elucidate the origin of transition-state barriers, EDA calculations were performed for some key saddle points populating the energy profiles.

Addition Reactions of Me3 SiCN with Aldehydes Catalyzed by Aluminum Complexes Containing in their Coordination Sphere O, S, and N Ligands.

The reaction of one equivalent of LAlH2 (1; L=HC(CMeNAr)2 , Ar=2,6-iPr2 C6 H3 , ß-diketiminate ligand) with two equivalents of 2-mercapto-4,6-dimethylpyrimidine hydrate resulted in LAl[(µ-S)(m-C4 N2 H)(CH2 )2 ]2 (2) in good yield. Similarly, when N-2-pyridylsalicylideneamine, N-(2,6-diisopropylphenyl)salicylaldimine, and ethyl 3-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate were used as starting materials, the corresponding products LAl[(µ-O)(o-C6 H4 )CN(C5 NH4 )]2 (3), LAlH[(µ-O)(o-C4 H4 )CN(2,6-iPr2 C6 H3 )] (4), and LAl[(µ-NH)(o-C8 SH8 )(COOC2 H5 )]2 (5) were isolated. Compounds 2-5 were characterized by (1) H and (13) C NMR spectroscopy as well as by single-crystal X-ray structural analysis. Surprisingly, compounds 2-5 exhibit good catalytic activity in addition reactions of aldehydes with trimethylsilyl cyanide (TMSCN).

B(C6F5)3-catalyzed dehydrogenative cyclization of N-tosylhydrazones and anilines via a Lewis adduct: a combined experimental and computational investigation.

Tris(pentafluorophenyl)borane-catalyzed dehydrogenative-cyclization of N-tosylhydrazones with aromatic amines has been disclosed. This metal-free catalytic protocol is compatible with a range of functional groups to provide both symmetrical and unsymmetrical 3,4,5-triaryl-1,2,4-triazoles. Mechanistic experiments and density functional theory (DFT) studies suggest an initial Lewis adduct formation of N-tosylhydrazone with B(C6F5)3 followed by sequential intermolecular amination of the borane adduct with aniline, intramolecular cyclization and frustrated Lewis pair (FLP)-catalyzed dehydrogenation for the generation of substituted 1,2,4-triazoles.

(PhC(NtBu)2Al)2(SiH2)4 six-membered heterocycle: comparable in structure to cyclohexane.

A silicon-aluminum heterocycle LAl(SiH2SiH2)2AlL (L = PhC(NtBu)2) (1) was prepared. Compound 1 exhibits a unique (N2Al)2(SiH2)4 centrosymmetric six-membered ring structure with a chair conformation, which is comparable with that of cyclohexane. Furthermore, two intermediate analogues, silylene-alane adduct LSi(AlMe3)-Si(AlMe3)L (2) and silylene-alane oxidative product [LAlHSiH2Mes]2 (3) were obtained. Compound 3 has an interesting arrangement of an Al-H and an SiH2 unit, which are in close vicinity to each other. 3 might be important to function as a catalyst, due to the already activated bridging Al-H bonds.

An unprecedented 1,4-diphospha-2,3-disila butadiene (-P[double bond, length as m-dash]Si-Si[double bond, length as m-dash]P-) derivative and a 1,3-diphospha-2-silaallyl anion, each stabilized by the amidinate ligand.

The first acyclic 4π-electron -P[double bond, length as m-dash]Si-Si[double bond, length as m-dash]P- motif with two four coordinate silicon substituents supported by the amidinate ligand and two coordinate phosphorus has been synthesized from the reaction of heteroleptic chlorosilylene LSiCl (1), TripPCl2 (Trip = 2,4,6-iPr3C6H2) and KC8 in a 1 : 1 : 3 ratio. The same reaction in a 1 : 2 : 6 ratio in the presence of one equivalent of 18-crown-6 ether affords the 1,3-diphospha-2-silaallyl anion.