Enhancing the Reaction Rates of Morita–Baylis–Hillman Reaction in Heterocyclic Aldehydes by Substitutions

The molecular origin of the experimentally observed pronounced difference in the rates of Morita–Baylis–Hillman (MBH) reaction in heterocyclic aldehydes, depending on the position of the formyl group, is investigated herein by using DFT‐based mechanistic studies and free energy computations. These calculations are based on the 1,4‐diazobicyclo[2.2.2]octane (DABCO)‐catalyzed MBH reaction of methyl acrylate with substituted 4‐ and 5‐isoxazolecarbaldehyde, which are slow‐ and fast‐reacting substrates, respectively. As a result of this study, we propose that by tailoring ring substitutions the reactivity of the formyl group for MBH reactions may be enhanced in slow‐reacting heterocyclic aldehydes. This proposition is demonstrated by enhancing the rate of the MBH reaction in 4‐isoxazolecarbaldehyde more than 10⁴‐fold by installing an ester substitution at the C‐3 position. Similarly, the reactivity of the formyl group towards the MBH reaction in substituted 3‐pyrazolecarbaldehyde and pyridinecarbaldehyde is shown to be increased several‐fold by a halo substitution. We also confirm that the reasons for different reactivities of heterocyclic aldehydes and the proposed scheme for improving the reaction rates remains valid for all the three mechanisms proposed for the MBH reaction, namely, Hill–Isaacs, McQuade, and Aggarwal.     

Nickel‐Catalyzed Mizoroki–Heck‐ versus Michael‐Type Addition of Organoboronic Acids to α,β‐Unsaturated Alkenes through Fine‐Tuning of Ligands

Various arylboronic acids reacted with activated alkenes in the presence of [Ni(dppe)Br₂], ZnCl₂, and H₂O in CH₃CN at 80 °C to give the corresponding Mizoroki–Heck‐type addition products in good to excellent yields. Furthermore, 1 equivalent of the hydrogenation product of the activated alkene was also produced. By tuning the ligands of the nickel complexes and the reaction conditions, Michael‐type addition was achieved in a very selective manner. Thus, various p‐ and o‐substituted arylboronic acids or alkenylboronic acid reacted smoothly with activated alkenes in CH₃CN at 80 °C for 12 h catalyzed by Ni(acac)₂, P(o‐anisyl)₃, and K₂CO₃ to give the corresponding Michael‐type addition products in excellent yields. However, for m‐substituted arylboronic acids, the yields of Michael‐type addition products are very low. The cause of this unusual meta‐substitution effect is not clear. By altering the solvent or phosphine ligand, the product yields for m‐substituted arylboronic acids were greatly improved. In contrast to previous results in the literature, the present catalytic reactions required water for Mizoroki–Heck‐type products and dry reaction conditions for Michael‐type addition products. Possible mechanistic pathways for both addition reactions are proposed.     

Divergent Pathways and Competitive Mechanisms of Metathesis Reactions between 3‐Arylprop‐2‐ynyl Esters and Aldehydes: An Experimental and Theoretical Study

Mechanistic studies of the reaction between 3‐arylprop‐2‐ynyl esters and aldehydes catalyzed by BF₃ ? Et₂O were performed by isotopic labeling experiments and quantum chemical calculations. The reactions are shown to proceed by either a classical alkyne–carbonyl metathesis route or an unprecedented addition–rearrangement cascade. Depending on the structure of the starting materials and the reaction conditions, the products of these reactions can be Morita–Baylis–Hillman (MBH) adducts that are unavailable by traditional MBH reactions or E‐ and Z‐α,β‐unsaturated ketones. ¹⁸O‐Labeling studies suggested the existence of two different reaction pathways to the products. These pathways were further examined by quantum chemical calculations that employed the DFT(wB97XD)/6‐311+G(2d,p) method, together with the conductor‐like screening model for realistic solvation (COSMO‐RS). By using the wB97XD functional, the accuracy of the computed data is estimated to be 1–2 kcal mol^?1, shown by the careful benchmarking of various DFT functionals against coupled cluster calculations at the CCSD(T)/aug‐cc‐pVTZ level of theory. Indeed, most of the experimental data were reproduced and explained by theory and it was convincingly shown that the branching point between the two distinct mechanisms is the formation of the first intermediate on the reaction pathway: either the four‐membered oxete or the six‐membered zwitterion. The deep mechanistic understanding of these reactions opens new synthetic avenues to chemically and biologically important α,β‐unsaturated ketones.     

DFT‐GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

The relatively large chemical shift differences observed in the ¹H NMR spectra of the anticholinergic drugs (?)‐scopolamine 1 and (?)‐hyoscyamine 2 measured in CDCl₃ are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas‐phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published ¹H and ¹³C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent. Copyright © 2010 John Wiley & Sons, Ltd.     

Asymmetric Hydrogenation with Highly Active IndolPhos–Rh Catalysts: Kinetics and Reaction Mechanism

The mechanism of the IndolPhos–Rh‐catalyzed asymmetric hydrogenation of prochiral olefins has been investigated by means of X‐ray crystal structure determination, kinetic measurements, high‐pressure NMR spectroscopy, and DFT calculations. The mechanistic study indicates that the reaction follows an unsaturate/dihydride mechanism according to Michaelis–Menten kinetics. A large value of K_M (K_M=5.01±0.16 M ) is obtained, which indicates that the Rh–solvate complex is the catalyst resting state, which has been observed by high‐pressure NMR spectroscopy. DFT calculations on the substrate–catalyst complexes, which are undetectable by experimental means, suggest that the major substrate–catalyst complex leads to the product. Such a mechanism is in accordance with previous studies on the mechanism of asymmetric hydrogenation reactions with C₁‐symmetric heteroditopic and monodentate ligands.     

Efficient Preparation of TMSCCl2Br and Its Use in Dichlorocyclopropanation of Electron‐Deficient Alkenes

The reaction of excess TMSCl and LiCCl₂Br at low temperature is a technically simple high yield route to TMSCCl₂Br. The latter is a stable source of the dichlorobromomethide carbanion, which undergoes 1,4‐addition with cyclic nitroalkenes and (E)‐fumarates leading to dichlorocyclopropanes after bromide expulsion. For nitrostyrenes the reaction arrests at the 1,4‐addition product. Low temperature NMR spectroscopy studies and DFT calculations suggest the formation of an “ate” species [(nitronate)SiFMe₃]^? which, upon boil‐off of TMSF at 10–20 °C, yields the cyclopropane. DFT calculations also support the experimental differences between fluoride and acetate as promotors.     

Building the “Phosphoindigo” Backbone by Oxidative Coupling of Phosphindolin‐3‐ones with Selenium Dioxide

Oxidative coupling of racemic 1‐ethoxy‐1‐oxophosphindolin‐3‐one ( 1 ) and its 5‐CF₃‐derivative 6 with SeO₂ furnishes 1,1′‐diphosphaindigo derivatives 5 and 7 as bis‐phosphinic esters, i. e. as P^V‐compounds. Like indigo and thioindigo, 5 and 7 exist in the E‐configuration; the crude products of 5 and 7 are mixtures of isomers that are trans‐ and cis‐configurated with respect to the relative orientation of the ester groups oat phosphorus. The structure of the centrosymmetric E‐P(R)P′(S) isomer [(E)‐trans‐isomer] of 5 was determined by X‐ray crystallography. Ester cleavage of 5 , followed by addition of triethylamine to bis‐phosphinic acid 9 (the 1,1,1′,1′‐tetroxide of “phosphoindigo”), furnishes the related bis‐triethylammonium salt 10 as a crystalline hydrate that exhibits an extended hydrogen bonding network.     

DFT‐GIAO 1H and 13C NMR prediction of chemical shifts for the configurational assignment of 6β‐hydroxyhyoscyamine diastereoisomers

¹H and ¹³C NMR chemical shift calculations using the density functional theory–gauge including/invariant atomic orbitals (DFT–GIAO) approximation at the B3LYP/6‐311G++(d,p) level of theory have been used to assign both natural diastereoisomers of 6β‐hydroxyhyoscyamine. The theoretical chemical shifts of the ¹H and ¹³C atoms in both isomers were calculated using a previously determined conformational distribution, and the theoretical and experimental values were cross‐compared. For protons, the obtained average absolute differences and root mean square (rms) errors for each comparison showed that the experimental chemical shifts of dextrorotatory and levorotatory 6β‐hydroxyhyoscyamines correlated well with the theoretical values calculated for the (3R,6R,2′S) and (3S,6S,2′S) configurations, respectively, whereas for ¹³C atoms the calculations were unable to differentiate between isomers. The nature of the relatively large chemical shift differences observed in nuclei that share similar chemical environments between isomers was asserted from the same calculations. It is shown that the anisotropic effect of the phenyl group in the tropic ester moiety, positioned under the tropane ring, has a larger shielding effect over one ring side than over the other one. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of Optically Enriched Spirocyclic Benzofuran‐2‐ones by Bifunctional Thiourea‐Base Catalyzed Double‐Michael Addition of Benzofuran‐2‐ones to Dienones

A highly enantioselective catalytic double‐Michael addition reaction of substituted benzofuran‐2‐ones with divinyl ketones promoted by readily accessible tertiary amine–thiourea Cinchona alkaloids has been developed. A number of optically enriched spirocyclic benzofuran‐2‐ones were prepared in very good yields (up to 99 %), diastereoselectivities (up to 19:1 d.r.), and very good enantioselectivities (up to 92 % ee). Density functional theory (DFT) calculations were performed to investigate the origin of stereoselectivity.     

Metal–Ligand Cooperation in Catalytic Intramolecular Hydroamination: A Computational Study of Iridium–Pyrazolato Cooperative Activation of Aminoalkenes

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2‐dimethyl‐4‐penten‐1‐amine by Cp*Ir chloropyrazole ( 1 ; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2 ?S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C?C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium–olefin linkage; 2) Ir? C bond protonolysis via stepwise transfer of the ammonium N? H proton at the zwitterionic [Cp*IrPz–alkyl] intermediate onto the metal that is linked to turnover‐limiting, reductive, cycloamine elimination commencing from a high‐energy, metastable [Cp*IrPz–hydrido–alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine–iridium bound 2 a ?S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen‐bonded network involving suitably aligned β‐basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β‐ or γ‐basic pyrazolato unit. As far as the route that involves amine N? H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N? H concurrent with N? C ring closure is disclosed as a favourable scenario. Although not practicable in the present system, this pathway describes a novel mechanistic variant in late transition metal–ligand bifunctional hydroamination catalysis that can perhaps be viable for tailored catalyst designs. The insights revealed herein concerning the operative mechanism and the structure–reactivity relationships will likely govern the rational design of late transition metal–ligand bifunctional catalysts and facilitate further conceptual advances in the area.     

Conformation of tert‐butoxy­carbonyl­glycyl‐dehydro­alanyl‐glycine methyl ester in the crystalline state and calculated in the gas phase

tert‐Butoxy­carbonyl­glycyl‐dehydro­alanyl‐glycine methyl ester (systematic name: methyl {2‐[(tert‐butoxycarbonylamino)­acetamido]prop‐2‐enamido}acetate) (Boc⁰‐Gly¹‐ΔAla²‐Gly³‐OMe), C₁₃H₂₁N₃O₆, has been structurally characterized by single‐crystal X‐ray diffraction and by density functional theory (DFT) calculations at the B3LYP/6–311+G** level. The peptide chain in both the solid‐state and calculated structures adopts neither β nor γ turns. All amino acid residues in the tripeptide sequence are linked trans to each other. The bond lengths and valence angles of the amino acid units in the crystal structure and gas phase are comparable. However, the conformation of the third glycyl residue (Gly³) is different in the crystalline state and in the gas phase. It is stabilized in the calculated structure by an additional intra­molecular short contact between Gly³ NH and methyl ester COMe groups.     

Reaction Mechanism and Regioselectivity of the Bingel–Hirsch Addition of Dimethyl Bromomalonate to La@C2v‐C82

We quantum chemically explore the thermodynamics and kinetics of all 65 possible mechanistic pathways of the Bingel–Hirsch addition of dimethyl bromomalonate to the endohedral metallofullerene La@C_2v‐C₈₂ that result from the combination of 24 nonequivalent carbon atoms and 35 different bonds present in La@C_2v‐C₈₂ by using dispersion‐corrected DFT calculations. Experimentally, this reaction leads to four singly bonded derivatives and one fulleroid adduct. Of these five products, only the singly bonded derivative on C23 could be experimentally identified unambiguously. Our calculations show that La@C_2v‐C₈₂ is not particularly regioselective under Bingel–Hirsch conditions. From the obtained results, however, it is possible to make a tentative assignment of the products observed experimentally. We propose that the observed fulleroid adduct results from the attack at bond 19 and that the singly bonded derivatives correspond to the C2, C19, C21, and C23 initial attacks. However, other possibilities cannot be ruled out completely.     

Theoretical study of silicon–sulfur clusters (SiS2)n− (n=1–6)

The possible geometrical structures and relative stability of silicon–sulfur clusters (SiS₂) (n=1–6) are explored by means of density functional theory (DFT) quantum chemical calculations. We also compare DFT with second‐order Møller–Plesset (MP2) and Hartree–Fock (HF) methods. The effects of polarization functions, diffuse functions, and electron correlation are included in MP2 and B3LYP quantum chemical calculations, and B3LYP is effective in larger cluster structure optimization, so we can conclude that the DFT approach is useful in establishing trends. The electronic structures and vibrational spectra of the most stable geometrical structures of (SiS₂)_n⁻ are analyzed by B3LYP. As a result, the regularity of the (SiS₂)_n⁻ cluster growing is obtained, and the calculation may predict the formation mechanism of the (SiS₂)_n⁻ cluster. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 81: 280–290, 2001     

Structural,Spectroscopic and Computational Examination of the Dative Interaction in Constrained Phosphine–Stibines and Phosphine–Stiboranes

A series of phosphine–stibine and phosphine–stiborane peri‐substituted acenaphthenes containing all permutations of pentavalent groups ?SbCl_nPh_4–n ( 5 – 9 ), as well as trivalent groups ?SbCl₂, ?Sb(R)Cl, and ?SbPh₂ ( 2 – 4 , R=Ph, Mes), were synthesised and fully characterised by single crystal diffraction and multinuclear NMR spectroscopy. In addition, the bonding in these species was studied by DFT computational methods. The P–Sb dative interactions in both series range from strongly bonding to non‐bonding as the Lewis acidity of the Sb acceptor is decreased. In the pentavalent antimony series, a significant change in the P–Sb distance is observed between ?SbClPh₃ and ?SbCl₂Ph₂ derivatives 6 and 7 , respectively, consistent with a change from a bonding to a non‐bonding interaction in response to relatively small modification in Lewis acidity of the acceptor. In the Sb^III series, two geometric forms are observed. The P–Sb bond length in the SbCl₂ derivative 2 is as expected for a normal (rather than a dative) bond. Rather unexpectedly, the phosphine–stiborane complexes 5 – 9 represent the first examples of the σ⁴P→σ⁶Sb structural motif.     

Catalytic Diastereoselective Tandem Conjugate Addition–Elimination Reaction of Morita–Baylis–Hillman C Adducts by C?C Bond Cleavage

Through the cleavage of the C? C bond, the first catalytic tandem conjugate addition–elimination reaction of Morita–Baylis–Hillman C adducts has been presented. Various S_N2′‐like C‐, S‐, and P‐allylic compounds could be obtained with exclusive E configuration in good to excellent yields. The Michael product could also be easily prepared by tuning the β‐C‐substituent group of the α‐methylene ester under the same reaction conditions. Calculated relative energies of various transition states by DFT methods strongly support the observed chemoselectivity and diastereoselectivity.     

Donor–Acceptor Complex Enables Alkoxyl Radical Generation for Metal‐Free C(sp3)–C(sp3) Cleavage and Allylation/Alkenylation

The alkoxyl radical is an essential and prevalent reactive intermediate for chemical and biological studies. Here we report the first donor–acceptor complex‐enabled alkoxyl radical generation under metal‐free reaction conditions induced by visible light. Hantzsch ester forms the key donor–acceptor complex with N ‐alkoxyl derivatives, which is elucidated by a series of spectrometry and mechanistic experiments. Selective C(sp³)‐C(sp³) bond cleavage and allylation/alkenylation is demonstrated for the first time using this photocatalyst‐free approach with linear primary, secondary, and tertiary alkoxyl radicals.     

Unprecedented Double aza‐Michael Addition within a Sapphyrin Core

A novel sapphyrin derivative was obtained from the reaction between a free‐base sapphyrin and dimethyl acetylenedicarboxylate (DMAD). The formation of the new compound involved a double aza‐Michael addition of two pyrrolic NH groups to a DMAD molecule, with the formation of a disubstituted ethano bridge. The NMR spectral data reveal a product with an unsymmetrical structure; DFT calculations provided support for a structure in which the ethano bridge links two adjacent pyrrole units. The present study provides a seemingly unprecedented example of an N,N′‐dinucleophile reacting with DMAD to form a heterocyclic compound in which the two N‐atoms are linked to the two sp³ carbon atoms derived from a substituted acetylene.     

Exploring the Molecular Structure of Imidazolium–Silica‐Based Nanoparticle Networks by Combining Solid‐State NMR Spectroscopy and First‐Principles Calculations

A DFT‐based molecular model for imidazolium–silica‐based nanoparticle networks (INNs) is presented. The INNs were synthesized and characterized by using small‐angle X‐ray scattering (SAXS), NMR spectroscopy, and theoretical ab initio calculations. ¹¹B and ³¹P HETCOR CP MAS experiments were recorded. Calculated ¹⁹F NMR spectroscopy results, combined with the calculated anion–imidazolium (IM) distances, predicted the IM chain density in the INN, which was also confirmed from thermogravimetric analysis/mass spectrometry results. The presence of water molecules trapped between the nanoparticles is also suggested. First considerations on possible π–π stacking between the IM rings are presented. The predicted electronic properties confirm the photoluminescence emissions in the correct spectral domain.     

Hydrogen Release from Dialkylamine–Boranes Promoted by Mg and Ca Complexes: A DFT Analysis of the Reaction Mechanism

Mg and Ca β‐diketiminato silylamides [HC{(Me)CN(2,6‐iPr₂C₆H₃)}₂M(THF)_n{N(SiMe₃)₂}] (M=Mg, n=0; M=Ca, n=1) were studied as precatalysts for the dehydrogenation/dehydrocoupling of secondary amine–boranes R₂HNBH₃. By reaction with equimolar quantities of amine–boranes, the corresponding amidoborane derivatives are formed, which further react to yield dehydrogenation products such as the cyclic dimer [BH₂?NMe₂]₂. DFT was used here to explore the mechanistic alternatives proposed on the basis of the experimental findings for both Mg and Ca amidoboranes. The influence of the steric demand of amine–boranes on the course of the reaction was examined by performing calculations on the dehydrogenation of dimethylamine–borane (DMAB), pyrrolidine–borane (PB), and diisopropylamine–borane. In spite of the analogies in the catalytic activity of Mg‐ and Ca‐based complexes in the dehydrocoupling of amine–boranes, our theoretical analysis confirmed the experimentally observed lower reactivity of Ca complexes. Differences in catalytic activity of Mg‐ and Ca‐based complexes were examined and rationalized. As a consequence of the increase in ionic radius on going from Mg²⁺ to Ca²⁺, the dehydrogenation mechanism changes and formation of a key metal hydride intermediate becomes inaccessible. Dimerization is likely to occur off‐metal in solution for DMAB and PB, whereas steric hindrance of iPr₂NHBH₃ hampers formation of the cyclic dimer. The reported results are of particular interest because, although amine–borane dehydrogenation is now well established, mechanistic insight is still lacking for many systems.