The Michael-Claisen domino (MCD) cyclization used in the lycopodine synthesis by Stork, was evaluated mechanistically using DFT calculations. Calculations suggest that a dianion is not formed, which conforms to classical dianion formation normally requiring strong kinetic bases. Instead ethoxide in ethanol produces a monoanionic species driving the MCD cyclization. This endeavor has opened up potential to expand the scope of this unique reaction and provide educational clarity.

On the basis of detailed theoretical studies of the mode of action of carbonic anhydrase (CA) and models resembling only its reactive core, a complete computational pathway analysis of the reaction between several isothiocyanates and methyl mercaptan activated by a thiolate-bearing model complex [Zn(NH3)3SMe]+ was performed at a high level of density functional theory (DFT). Furthermore, model reactions have been studied in the experiment using relatively stable zinc complexes and have been investigated by gas chromatography/mass spectrometry and Raman spectroscopy. The model complexes used in the experiment are based upon the well-known azamacrocyclic ligand family ([12]aneN4, [14]aneN4, i-[14]aneN4, and [15]aneN4) and are commonly formulated as ([Zn([X]aneN4)(SBn)]ClO4. As predicted by our DFT calculations, all of these complexes are capable of insertion into the heterocumulene system. Raman spectroscopic investigations indicate that aryl-substituted isothiocyanates predominantly add to the C═N bond and that the size of the ring-shaped ligands of the zinc complex also has a very significant influence on the selectivity and on the reactivity as well. Unfortunately, the activated isothiocyanate is not able to add to the thiolate-corresponding mercaptan to invoke a CA analogous catalytic cycle. However, more reactive compounds such as methyl iodide can be incorporated. This work gives new insight into the mode of action and reaction path variants derived from the CA principles. Further, aspects of the reliability of DFT calculations concerning the prediction of the selectivity and reactivity are discussed. In addition, the presented synthetic pathways can offer a completely new access to a variety of dithiocarbamates.

The influence of substituents at the allene skeleton on the rate-determining step of the reaction with nucleophiles catalyzed by biomimetic zinc complexes was investigated with quantum chemical (especially DFT) methods. Additional examinations were applied to derivatives of the zinc hydroxide complex modeled in analogy to the catalytic center of carbonic anhydrase. Especially suitable substituents in the allene moiety can lead to a significant lowering of the activation barrier. Further we demonstrate that by the application of this principle of a bioanalogous enhancement of reactivity other nucleophiles instead of the biological substrate can also be reactants in completely closed catalytic reaction cycles.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 1 can be converted into various products such as guanidines or bis(azolyl)alkanes. However, they also react with hydroxide ions in aqueous solution to form novel heterocyclic-substituted ureas 2a-i. The yields were increased from moderate to good or excellent in the presence of excess guanidine 3. The assumption that hydrogen-bonded intermediate encounter complexes EC are formed gives a reasonable explanation for the observed reaction path. The molecular structures of some of the crystalline products 2 were determined by X-ray analysis. Furthermore, with copper(II) a dinuclear complex 8 is formed with the two metal ions in a distorted octahedral environment; a water molecule acts as a bridging ligand between the Cull ions. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

In the title compound, [Zn(C(11)H(26)N(4))(C(11)H(9)S)]ClO(4), the Zn(II) atom is five-coordinated by four N atoms from a neutral 1,4,8,12-tetra-azacyclo-penta-decane aza-macrocycle mol-ecule, and one S atom from an azulenylmethane-thiol-ate ligand. Only monomers are found in the crystal. The coordination geometry can be described as trigonal bipyramidal, with the thiol-ate group in an equatorial position. The Zn-N and Zn-S distances are in the usual ranges for this type of complex.

Unsymmetrical chiral secondary vicinal diamines were synthesized by applying a modified three-step reaction. The key step in this sequence is a primary amine mediated ring opening reaction of a diastereomeric oxazolidinone derivative. A possible mechanism for this step is described.

Abstract Formaldehyde reacts with diformamide (10) to give N-(hydroxymethyl)diformamide (11), which upon treatment with thionylchloride yields N-(chlormethyl)diformamide (12) together with small amounts of oxydimethylenebis(diformamide) (13). Various diformylamine derivatives, such as diformylaminomethyl formiate (14), diformylaminomethylisothiocyanate (15) and the N-diformylaminomethylated guanidinium salt 16, can be prepared from 12. Bis(diformylamino) methane (7) can be obtained by the reaction of sodium diformamide (8) with either 1-(chloromethyl)pyridinium chloride (9) or N-(chloromethyl)diformamide (12) in acetonitrile. The action of tris(chloromethyl) amine (18) on sodium diformamide (8) affords tris(diformylaminomethyl)amine (19). The constitution of the compounds 7, 11 and 19 was confirmed by crystal structure determination. The nature of the products from the reactions of aromatic compounds with 12 depends on the Lewis acid which is used as activator. Thus the N-benzylformamides 20a, b can be obtained from toluene and mesitylene and 12/BF3-ether, whereas 1,2,4-trimethoxybenzene is formylated by 12/AlCl3 to give the aldehyde 22. Interestingly enough, a novel and efficient formylating reagent resulted from these investigations: bis(diformylamino)methane (7), which can be activated by Lewis acids, e. g. AlCl3. The scope of this procedure is comparable with that of the Olah-formylation method (formylfluoride/BF3).

The aim of our present investigation is to unravel the general mode of biomimetic activation of a wide variety of cumulenes by carbonic anhydrase (CA) models. Carbonic anhydrases allow the specific recognition, activation and transfer not only of CO2 but also of heteroallenes X=C=Y such as the polar or polarizable examples COS, CS2, H2CCO, and RNCS. Therefore, this enzyme class fulfils the requirements of excellent catalysts with a wide variety of important applications. Can this be extended to the isoelectronic but less reactive allene molecule, H2C=C=CH2 and extremely simplified models as mimetic concept for active center of the carbonic anhydrase? Allene is a waste product in the refinery, i.e. the C3-cut of the naphtha distillation; therefore, any addition product that can be obtained from allene in high yields will be of significant value. We investigated the complete catalytic cycle of a very simple model reaction, the hydration of allene, using density functional theory. Additionally, calculations were performed for the uncatalyzed reaction. There are two possible ways for the nucleophilic attack leading to different products. The zinc hydroxide complex and the water molecule can react at the central or the terminal carbon atoms (positional selectivity), the resulting products are 2-propen-1-ol and propen-2-ol, respectively, acetone. The calculations indicate a significant lower energy barrier for the rate determining step of the formation of propen-2-ol and therefore a well-expressed regioselectivity for the addition of such small molecules. The zinc complex has a pronounced catalytic effect and lowers the activation barrier from 262.5 to 123.9 kJ/mol compared with the uncatalyzed reaction. This work suggests the most probable paths for this reaction and discloses the necessity for the development of novel catalysts.

The macrocyclic ligand [13]aneN(4) (L1, 1,4,7,10-tetra-azacyclotridecane) was reacted with Zn(II) perchlorate and CO2 in an alkaline methanol solution. It was found that, by means of subtle changes in reaction conditions, two types of complexes can be obtained: (a) the mu(3) carbonate complex 1, {[Zn(L1)](3)(mu(3)-CO3)}(ClO4)(4), rhombohedral crystals, space group R3c, with pentacoordinate zinc in a trigonal bipyramidal enviroment, and (b) an unprecedenced dimeric Zn(II) carbamate structure, 2, [Zn(L2)](2)(ClO4)(2), monoclinic crystals, space group P2(1)/n. The ligand L2 (4-carboxyl-1,4,7,10-tetra-azacyclotridecane) is a carbamate derivative of L1, obtained by transformation of a hydrogen atom of one of the NH moieties into carbamate by means of CO2 uptake. In compound 2, the distorted tetrahedral Zn(II) coordinates to the carbamate moiety in a monodentate manner. Most notably, carbamate formation can occur upon reaction of CO2 with the [ZnL1](2+) complex, which implicates that a Zn-N linkage is cleaved upon attack of CO2. Since complexes of tetra-azamacrocycles and Zn(II) are routinely applied for enzyme model studies, this finding implies that the Zn-azamacrocycle moiety generally should no longer be considered to play always only an innocent role in reactions. Rather, its reactivity has to be taken into account in respective investigations. In the presence of water, 2 is transformed readily into carbonate 1. Both compounds have been additionally characterized by solid-state NMR and infrared spectroscopy. A thorough comparison of 1 with related azamacrocycle ligated zinc(II) carbonates as well as a discussion of plausible reaction paths for the formation of 2 are given. Furthermore, the infrared absorptions of the carbamate moiety have been assigned by calculating the vibrational modes of the carbamate complex using DFT methods and the vibrational spectroscopy calculation program package SNF.

Based upon our preceding studies of the hydration of CO2, COS and CS2, accelerated by the carbonic anhydrase (CA) using simplified [ZnL3OH](+) complexes as model catalysts, we calculated the hydration mechanisms of both the uncatalyzed and the [ZnL3OH](+)-catalyzed reactions (L = NH3) of isothiocyanates RNCS on the B3LYP/6-311+G(d,p) level of theory. Interestingly, the transition state for the favored metal mediated reaction with the lowest Gibbs free energy is only slightly higher than in the case of CO2 (depending on the attacking atom (N or S). Calculations under inclusion of solvent corrections show a reduction of the selectivity and a slight decrease of the Gibbs free energy in the rate-determining steps. The most plausible pathway prefers the mechanism via a Lindskog proton-shift transition state leading to the thermodynamically most stable product, the carbamatic-S-acid. Furthermore, powerful electron withdrawing substituents R of the cumulenic substrates influence the selectivity of the reaction to a significant extent. Especially the CF3-group in trifluoromethylisothiocyanate reverses the selectivity. This investigation demonstrates that reaction principles developed by nature can be translated to develop efficient catalytic methods, in this case presumably for the transformation of a wide variety of heterocumulenes aside from CO2, COS and CS2.

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In the title compound, [Zn(C11H26N4)(C11H9S)]ClO4, the ZnII atom is five-coordinated by four N atoms from a neutral 1,4,8,12-tetraazacyclopentadecane aza-macrocycle molecule, and one S atom from an azulenylmethanethiolate ligand. Only monomers are found in the crystal. The coordination geometry can be described as trigonal bipyramidal, with the thiolate group in an equatorial position. The Zn—N and Zn—S distances are in the usual ranges for this type of complex.

A one pot synthesis of the 3,3-dimethylacroyl enol ester function found in the vibsane type diterpenes has been developed based on the Anders–Gaßner variant of the Wittig reaction (AGW reaction). This method uses easily accessible acyloxyalkylidene phosphoranes and a variety of aldehydes.

In this study, we focus on the structure-re activity relationship of cationic zinc thiolate complexes with the general formula [Zn(L-n)(SR)]ClO4 (L-n: n-dentate azamacrocyclic ligand; R = phenylmethyl). The complexes feature macrocyclic ligands with ring sizes varying from 11 to 16 atoms and possess three or four nitrogen donors (three of them containing one tertiary nitrogen). Thiol methylations with methyl iodide have been performed in order to determine the relative reactivities, because this reaction has been used before to investigate zinc thiolate reactivity and therefore allows comparison of our results with literature data. The kinetic behaviour was investigated in nitromethane and dichloromethane and was found to be second order in all cases. The observed rate constants vary in the range of k(2) = 2.46-55.28 x 10(-3) m(-1)s(-1) in nitromethane and k(2) = 0.23-7.35 x 10(-3) M(-1)s(-1) in dichloromethane at 300 K. Furthermore, the structures of all thiolate complexes were optimised at the B3LYP/6-311+G(d) level of theory. Natural bond orbital (NBO) analyses were performed to obtain information on partial charges of the heteroatoms and energies of a lone pair in a p-type orbital at the zinc-bound sulfur. In order to elucidate which parameters determine reactivity, selected structural and electronic parameters were correlated with the experimental rate constants. As a result, we found that the reaction is controlled predominantly by frontier orbital energy in dichloromethane and by charge in nitromethane. However, we observed that electronic reactivity control can be overridden by the degree of steric obstruction of the zinc ion, which directly depends on ring size and configuration of the ring nitrogens. The complex [Zn(cyclen)(SR)]ClO4 (5) can therefore not be included in any of the correlations; steric constraint imposed by the comparably small ring system causes an extraordinarily increased reactivity. In turn, this finding provides a new rationale for the high reactivity reported for the cyclen complex [Zn(cyclen)(OH)](+), which has been used as a model for carbonic anhydrase in previous studies. (c) Wiley-VCH Verlag GmbH & Co. KGaA.

Carbonic anhydrase (CA) is known to react with carbonyl sulfide, an atmospheric trace gas, whereby H(2)S is formed. It has been shown that, in the course of this reaction, the active catalyst, the His(3)ZnOH structural motif, is converted to its hydrosulfide form: His(3)ZnOH+COS-->His(3)ZnSH+CO(2). In this study, we elucidate the mechanism of reactivation of carbonic anhydrase (CA) from its hydrosulfide analogue by using density functional calculations, a model reaction and in vivo experimental investigation. The desulfuration occurs according to the overall equation His(3)ZnSH+H(2)O right harpoon over left harpoon His(3)ZnOH+H(2)S. The initial step is a protonation equilibrium at the zinc-bound hydrosulfide. The hydrogen sulfide ligand thus formed is then replaced by a water molecule, which is subsequently deprotonated to yield the reactivated catalytic centre of CA. Such a mechanism is thought to enable a plant cell to expel H(2)S or rapidly metabolise it to cysteine via the cysteine synthase complex. The proposed mechanism of desulfuration of the hydrosulfide analogue of CA can thus be regarded as the missing link between COS consumption of plants and their sulfur metabolism.

The crystal structure of the title compound, [Zn(C 30 H 28 BN 6 )(C 7 H 7 S)], is closely related to a series of other tripod zinc thiolates. The Zn atom adopts a very distorted tetrahedral coordination geometry. In addition to the crystallographic data, 11 B NMR as well as 11 B-decoupled 1 H NMR data are provided. A proton shift for the boron-bound hydride (5.15 p.p.m.) of a pyrazolylborato ligand is reported for the first time.

In the title compound, C 18 H 28 N 2 O 4 , the molecule displays a partially eclipsed conformation with an N—C—C—N torsion angle of 67.93 (s.u.?) ° linking the two ethoxycarbonylcyclopentenyl groups. This conformation is different from the staggered conformation observed in the related N , N ′-ethylenediamine with a cycloalkene residue. Molecules are linked by two different N—H...O hydrogen bonds, generating sheets parallel to the (110) plane.

Some aspects of the catalytic mechanism of HCA have been investigated. Either a zinc-bound water or a zinc-bound hydroxide has been considered as a nucleophile attacking CO 2. No reaction path exists in the former case, while a transition state for the nucleophilic attack has been located in the latter (barrier of 7.6  kcal  mol−1). This activation energy is determined by the breaking of the hydrogen-bond network that shields the zinc-bound hydroxide when the CO 2 molecule approaches the reaction center. No ambiguity exists about the mechanism for the internal rearrangement of the zinc–bicarbonate complex. The rotation pathway (Lindskog mechanism) proposed by many authors is too energy demanding since it causes the breaking of the hydrogen-bond network around the bicarbonate. The only possible rearrangement mechanism is a proton transfer (Lipscomb) that occurs in two steps (each step corresponding to a double proton transfer) and involves the Thr199 residue as a proton shuttle.

The title compound, [Zn(C 7 H 7 S)(C 9 H 21 N 3 )]SCN, features a cationic Zn complex with the metal atom in a distorted tetrahedral environment. The crystal packing is stabilized by N—H...N and N—H...S hydrogen bonds. However, one of the amino H atoms is not involved in hydrogen bonding.