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The cycloaddition of simple alkyl-substituted guanidine derivatives is an interesting approach toward polycyclic superbases and guanidine-based organocatalysts. Due to the high nucleophilicity of guanidines, an aza-Michael reaction with dienophiles is more common and presents a huge obstacle in achieving the desired synthetic goal. Our preliminary investigations indicated that the proton could act as a suitable protecting group to regulate the directionality of the reaction. To investigate the role of the protonation state and type of anion, the reactivity of furfuryl guanidines with dimethyl acetylenedicarboxylate was explored. Furfuryl guanidines showed a strong reaction dependence on the nucleophilicity of the counterion and the structure of guanidine. While the reaction of DMAD with the guanidinium halides provided products of an aza-Michael addition, Diels–Alder cycloaddition occurred if non-nucleophilic hexafluorophosphate salts were used. Depending on the structure and the reaction conditions, oxanorbornadiene products underwent subsequent intramolecular cyclization. A tendency toward intramolecular cyclization was interpreted in terms of the pKa of different positions of the guanidine functionality in oxanorbornadienes. New polycyclic guanidines had a slightly decreased pKa in acetonitrile and well-defined geometry suitable for the buildup of selective sensors.

A simple but efficient computational approach to calculate p

Sustainable organic synthesis Guanylation of aromatic amines and thermal electrocyclization could be carried out by consecutive employment of sustainable synthetic methods - mechanosynthesis and microwave irradiation. Quantum-chemical calculations DFT methods suggest the mechanistic details, with crucial involvement of solvation in the key processes - elimination of Boc substituent and 1, 5 H-shift. Relative reactivities and regioselectivities of series of aromatic guanidines was predicted correctly.

A simple but efficient computational approach to calculate pKa in acetonitrile for a set of phosphorus, nitrogen, and carbon bases was established. A linear function that describes relations between the calculated ΔG’a.sol(BH+) and pKa values was determined for each group of bases. The best model was obtained through the variations in the basis set, in the level of theory (density functionals or MP2), and in the continuum solvation model (IPCM, CPCM, or SMD). The combination of the IPCM/B3LYP/6-311+G(d,p) solvation approach with MP2/6-311+G(2df,p)//B3LYP/6-31G(d) gas-phase energies provided very good results for all three groups of bases with R2 values close to or above 0.99. Interestingly, the slopes and the intercepts of the obtained linear functions showed significant deviations from the theoretical values. We made a linear plot utilizing all the conducted calculations and all the structural variations and employed methods to prove the systematic nature of the intercept/slope dependence. The interpolation of the intercept to the ideal slope value enabled us to determine the Gibbs energy of the proton in acetonitrile, which amounted to −258.8 kcal mol−1. The obtained value was in excellent agreement with previously published results.

The cycloaddition strategy was employed in order to obtain a 7-oxanorbornene framework substituted with a guanidine moiety or its precursor functional groups: protected amine or thiourea. In order to optimize the conditions for the cycloaddition, several environmentally-friendly methods—microwave assisted organic synthesis, high pressure synthesis, high speed vibrational milling, and ultrasound assisted synthesis—were employed. The outcomes of the cycloaddition reactions were interpreted in terms of endo/exo selectivity, the conversion of the reactants to the product, and the isolated yields. In general, our results indicated the HP and HSVM approaches as the methods of choice to give good yields and conversions.

A series of aryl-substituted guanidines revealed a pKa of about 10 in aqueous medium, thus positioning themselves between the more basic aliphatic guanidines (pKa > 13) and the acidic guanidinocarbonyl-pyrrole (pKa 6). The study revealed that for the biorelevant (micromolar) affinity toward ds-DNA and ds-RNA, the minimal size of the aryl-unit is anthracene. Further aryl-increase (pyrene, porphyrin) did not result in a stronger affinity toward ds-DNA/RNA, nor give significant thermal stabilisation of the DNA/RNA double helix, thus suggesting that aromatic stacking interactions between the compounds and DNA/RNA are not the dominant binding interaction. Generally, the results suggested that aryl-guanidines bind to DNA/RNA grooves by a combination of hydrophobic, electrostatic, H-bonding and van der Waals interactions, whereby fluorescence of the two largest aromatics (pyrene, porphyrin) was highly sensitive in the fine probing of the DNA/RNA groove properties. In addition, pyrene and porphyrin analogues at excess polynucleotide binding sites aggregated within the polynucleotide groove, yielding fine recognition between various ds-DNA and ds-RNA by induced circular dichroism signals.

In this study biodiesel was produced from waste sunflower cooking oil and ethanol using N,N′,N″-tris(3-dimethylaminopropyl)-guanidine as new catalyst, which allows to avoid unwanted side-reaction of saponification. The influence of process variables on the conversion was investigated using experimental design and response surface methodology. Independent factors were varied in the following range: molar ratio of alcohol/oil from 3:1 to 15:1; catalyst concentration from 0.5 to 3 wt%; reaction temperature from 40 to 80 °C; and reaction time from 40 to 200 min. An empirical model of the process was developed. With this model and the goals of minimizing the independent factors in the tested range and maximizing the conversion, the optimization resulted in the following conditions: 1.13 wt% of catalyst, a molar ratio of 11.16:1, temperature of 67.96 °C, and a reaction time of 80 min. With those optimal conditions, the conversion predicted by the model was 94.6%.

(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2pG, 2pA, 2mG and 2mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC50 values of 5–30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV–Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC50 values show higher binding affinities towards BSA. Compound 2mG with value of IC50 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2pG, 2pA, 2mG and 2mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.

Solid state ball milling was used in guanidinylation reactions of aromatic amines with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine reagent. Reaction conditions are advantageous, and in general reactions proceed in significantly shorter reaction times and in higher yields than under the conventional solution conditions. Mechanochemical conditions were also successfully applied to the cleavage of N-Boc protecting group.

The gas-phase basicities (GB) of 7 biguanides were measured by the equilibrium and the entropy corrected kinetic methods. The experimental data were compared with the GB values calculated at B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) level of theory. Calculated GB values for biguanides correlate well with the experimental data and lie on the same regression line as guanidine derivatives. All biguanides belong to the class of superbases having GB above 1000 kJ mol−1 and being comparable or more basic than the most basic guanidines known. The highest GB of 1103 kJ mol−1 was determined for the bis-dimethylaminomethylene-2,3-bis-(3-dimethylaminopropyl)guanidine (biguanide 4) in which two intramolecular hydrogen bonds (IMHB) can be formed in the protonated form. For selected biguanides and guanidines, contribution of IMHB to the GB was calculated for two conformations with different hydrogen bonding motifs (6- and 8- membered pseudocyclic substructure). In conjugated acids of biguanides having two 3-dimethylaminopropyl or 3-methoxypropyl substituents, conformational preference is determined by maximizing number of possible IMHBs. Hydrogen bond stabilization enthalpies were also calculated using aforementioned B3LYP as well as M06-2X/6-311++G(3df,2p)//B3LYP/6-31G(d) model and compared to the values obtained for guanidine derivatives. Slightly weaker hydrogen bonds in biguanides with respect to guanidines were ascribed to larger steric congestion while the impact of more extensive delocalization area was found negligible.

Natural and synthetic guanidines are drawing a much interest due to their interesting physico- chemical properties.[1] Guanidines are commonly occurring functionality in nature, therefore, a lot of research has been done in bioorganic chemistry with the aim to discover and design pharmacologically active guanidine derivatives. [2] Also, the very high basicity (superbasicity) of neutral organic guanidine compounds is commonly employed in homogeneous catalysis.[1] There are already many different studies on basicity of different guanidine derivatives with the focus on finding new organic superbases and developing synthesis of those compounds.[3] Among various examples, 1, 5, 7-triazabicyclo[4.4.0]dec-5-ene (TBD) is well-known, commercially available cyclic superbase. Herein, we report our methodical study of the gas-phase basicity (GB) of various cyclic guanidine derivatives by Density Functional Theory (DFT) calculations using the B3LYP functional. Considered guanidines differ in the number of nitrogen atoms incorporated in heterocyclic rings as well as in the size of heterocyclic rings (Scheme 1). To locate the most stable structures of the neutral and protonated forms, a set of possible conformations were optimized. The most important structural parameters beneficially contributing to the stability of the structure are identified.

A series of benzoylguanidinium salts was prepared and the changes in UV/Vis spectra, triggered by the presence of anions, were investigated. All compounds undergo deprotonation with basic anions like dihydrogenphosphate and acetate in acetonitrile. The most pronounced spectral changes were obtained by deprotonation of N1 -benzoyl-N3 -(p-nitrophenyl) guanidinium chloride which shows the naked-eye visible color change from colorless to yellow. Measured pKa (BH+ ) in acetonitrile ranges from 12-16, which is comparable to the pyridinium cations. The proton transfer equilibria were also tested in acetonitrile/water mixture where all but the most acidic derivatives showed pKa (BH+ ) of 4-6 units which corresponds to apparent association constants of 104 -106 dm3 mol-1 . UV/Vis spectra of neutral and protonated forms were modelled by the TD-DFT approach using CAM-B3LYP and PBE0 functionals and compared to CC2 results. In the case of CAM-B3LYP, a parameter ω, defining amount of long-range exchange correction, was varied to achieve the best agreement with the experimental spectra. The optimized ω parameters are 0.10 a0 -1 for neutral benzoylguanidines and 0.20 a0 -1 for neutral nitrobenzoyl and protonated systems. The larger ω parameter in the latter is ascribed to more pronounced charge transfer character of the HOMO-LUMO transition - the one responsible for the lowest energy absorption band.

Bioconjugate bidentate ligands 2−10 were 8 obtained by tethering triphenylphosphanecarboxylic acid to amino acid substituted spacers with different flexibility, ranging from a rigid enediyne-based β-turn inducer to flexible linear aliphatic chains with up to eight carbon atoms. The 21 synthesized ligands revealed up to 81% ee selectivity in rhodium-catalyzed asymmetric hydrogenation of α, β-unsaturated amino acids. The key feature of the catalysts is the prochiral coordination sphere of the catalytic metal while the chirality is transmitted by “backdoor induction” from distant hydrogen-bonded amino acids. DFT calculations were applied to study the structure and relative stability of the precatalytic organometallic Rh(I) complexes, with particular emphasis on hydrogen-bonded secondary structures.

New guanidine-derived superbases with TBD-functionalized alkyl side chains have been developed using a computational DFT approach. Exploiting the high hydrogen bond basicity of TBD allowed ac-cess to systems with strong charge-assisted intramolecular hydrogen bonds in the protonated state. The enhanced stability of such guanidines is mirrored in their gas-phase basicities, which cover the range from 1044−1168 kJ mol−1, depending on the number of alkyl side chains, the type of alkyl spac-er and the hydrogen-bonding pattern.

The gas-phase basicities (GB) and proton affinities (PA) of six novel guanidine derivatives were measured by the entropy corrected kinetic method. The proton affinities of the dimethylaminopropyl and methoxypropyl guanidine derivatives 8–12, as described earlier in Ref. [5] , were refined employing a new set of reference bases and were found to be in good agreement with previously published values. Their GB values were also evaluated. In this way a useful set of potential reference bases with GBs in the range of 1037–1079 kJ mol−1 was developed allowing their use in further measurements of more basic compounds. The experimentally determined gas-phase basicities correlate well with the pKHB values of the hydrogen bond accepting functional groups within the heteroalkyl side-chain(s). Trends in the changes in the measured GB and PA values for the set of 25 nitrogen bases including the investigated ones were compared with the computed data arrived with the following methods: B3LYP/6-311 + G(2df,p)//B3LYP/6-31 + G(d,p), MP2/6-311 + G(d,p)//B3LYP/6-31 + G(d,p), BMK/6-311 + G(d,p)//B3LYP/6-31 + G(d,p) and M06-2X/6-311 + G(d,p)//B3LYP/6-31 + G(d,p). It is shown that the B3LYP and BMK functionals slightly overestimate the experimental values for 2-(2-pyridyl)ethyl substituted bases, while the M06-2X, and in particular the MP2 results, are in much better agreement with the absolute GB values.

A series of hexasubstituted biguanides was synthetized employing non-conventional and environmentally friendly methods. Their properties were studied computationally (basicity) and experimentally (basicity and catalytic properties in transesterification reaction).

This work presents a correlation method that uses 1H NMR spectra for determining the conversion during transesterification of vegetable oil with 10 alcohols: methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, isobutanol, 1- pentanol, isopentanol, 1-hexanol, 1-heptanol, 1- octanol, 1-decanol, 1-dodecanol, and benzyl alcohol. Conversions ranging from 70 to 99%, depending on primary alcohol used, are obtained using organic catalyst N, N′, N″-tris(3- (dimethylamino)propyl)guanidine. Catalysts, alcohols, and intermediate products can cause signal overlapping, debilitating the use of the conventional 1H NMR method. Thus, our method uses the correlation between the triplet signal of α- carbonylmethylene and two signals of unsaturated parts of the fatty acid chain, where signal overlapping does not occur, hence, adding robustness and flexibility to the method. The method is applicable for unsaturated oils and is not affected by the amounts of residual alcohol, catalyst, or intermediate products, making it ideal for conversion determination and in situ monitoring of complex mixtures. In addition, we present a systematic analysis of the 1H NMR spectra of biodiesels produced with the mentioned alcohols.

International audience; UV/vis spectra of phenylguanidine (PHGU) in the gas phase and in acetonitrile have been simulated by TD-DFT calculations. Several DFT hybrid and long-range corrected functionals were tested with respect to CASPT2 gas phase calculations. Solvent effects were considered using polarizable continuum model (PCM) and compared with the measured data in acetonitrile. Comparison with isoelectronic phenylurea and related phenyltiourea was done as well. The PBE0 and long-range corrected CAM-B3LYP functionals were selected to investigate the effect of protonation on the excitation energies and absorption intensities of PHGU and several guanidine derivatives with different aromatic chromophoric groups (naphthyl, anthracenyl, quinolinyl, anthraquinonyl, and coumarinyl). Also, the effect of complexation and specific interactions through hydrogen bonds with different anions was examined. It was shown that the protonation of the guanidine subunit shifts the low energy absorption bands toward higher energies (hypsochromic shift). The shift is reduced upon complexation with anions. In phenylguanidine salts, λmax values are correlated to the anion basicity and strength of H-bonding. The observed changes diminish upon increase of chromophoric size (naphthyl, anthracenyl). Theoretical predictions of UV/vis spectra correlate well with experimentally measured spectra of selected guanidine derivatives and their salts.

A facile synthesis of methyl carbamates from primary amines and dimethyl carbonate has been achieved at room temperature using high pressure. High-pressure synthesis of methyl carbamates described herein provides access to the target molecules in an efficient and environmentally friendly way without solvent or catalyst. Better conversion and selectivity than previously published procedures were obtained.

The effect of substituents directly bound to the deprotonation site (C-7) on the acidity of cyclopropabenzene was studied using the MP2/6–31+G* method. The studied substituents encompass a variety of π- and σ-accepting groups including the highly electronegative fluorine atom. It is shown that all substituents enhance the acidity of cyclopropabenzene with the effect being the smallest (0.02 kcal mol−1) for the methyl group and the largest (33.7 kcal mol−1) for the hydrosulfonyl group. It is further shown that the α-subsituents employed stabilize the cyclopropabenzenyl anion less efficiently than the cyclopropenyl anion, with the effect being more pronounced for the substituents acting via inductive/field effects. This is attributed to the fact that attachment of inductively/field acting substituents to the carbanionic site predominantly stabilize the cyclopropenyl anion by increasing the s character of the lone pair, diminishing the antiaromatic character of the three-membered ring at the same time. Hence these two effects are operative in concert. The opposite occurs in related cyclopropabenzenyl anions. Here, the rehybridization at the carbanionic center does stabilize the lone pair, but decreases the anionic resonance of the whole system, because of a decrease in overlap between the lone pair and the π-AO of the annelated bond. The reverse picture holds for the conjugatively acting substituents. Copyright © 2005 John Wiley & Sons, Ltd.

An overview of our recent work on cycloproparenyl anions is given. Preparation, the electronic structure, and the properties of the progenitor of the series, cyclopropabenzenyl anion, are discussed. It is shown that the cyclopropabenzenyl anion is by ca. 145 kJ mol-1 more stable than the parent cyclopropenyl anion according to results of the MP2/6-31+G(d) calculations. This finding was attributed to a delicate balance of two opposing effects: (a) propensity of the aromatic ring to alleviate unfavorable 4π electron interaction within the three-membered ring by the anionic resonance effect and (b) a pyramidalization of the anionic center, which tends to maximize the s-character of the lone pair. We have also shown that stability of the cyclopropabenzenyl anion could be considerably enhanced by substitution of the aromatic ring with fluorine and cyano groups, as well as by a linear extension of the aromatic backbone. Finally, the impact of the fusion of additional cyclopropenyl ring to the benzene moiety to acidity of the benzylic position in cyclopropabenzene is discussed.

Alkaneoxodiazonium ions (R—NNO)+ and (R—O—N2)+, which are closely analogous to alkanediazonium ions (R—N2)+, were detected as reactive intermediates in acid-catalysed reactions of nitrosohydroxylamines and deamination-type reactions. The isomers were compared by high-level MO investigations of the reactions of nitrous oxide with cationic electrophiles H+, CH3+, Me3C+ and PhCH2+. Strongly bonded species are formed in reactions with the powerfully electrophilic H+ and CH3+, and the resulting ions differ considerably in stabilities; less stable species are formed with Me3C+ and PhCH2+ and the complexes so formed have similar stabilities. Two isomers of Ph(N2O)+, analogous to phenyldiazonium ion, PhN2+, are calculated to be stable ions with the end-N-bonded isomer being preferred over the O-bonded ion at the MP4(SDQ)/6–311G(d,p)//MP2(fc)/6–31G(d,p) and G3 levels of theory. Both are non-planar with the phenyl ring at 90° to the non-linear N2O residue. Syntheses of salts of Ar(N2O)+ are now planned. Copyright © 2003 John Wiley & Sons, Ltd.

1 H -Cyclopropa[b]naphthalene ( 3H ) and 2-methylnaphthalene ( 6H ) were deprotonated by fluoride ion in a Fourier transform mass spectrometer, and their acidities were measured via equilibrium techniques (Δ G ° acid =357.5±2.1 kcal mol −1 ( 3H ) and 365.2±2.1 kcal mol −1 ( 6H ), Δ H ° acid =365.1±2.1 kcal mol −1 ( 3H ) and 372.7±2.1 kcal mol −1 ( 6H )). These results were modeled by MP2 and BVWN5 calculations, and additional computations were carried out on benzocyclopropene ( 1H ), toluene ( 2H ), 1 H -cyclopropa[a]naphthalene ( 4H ), and 1-methylnaphthalene ( 5H ). The stability of the conjugate bases of 3H and 4H are examined and their aromatic vs. antiaromatic nature is considered.

The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A(-)) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group (m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 (m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes Hβ proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-Cα bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines.

1-Phenylcyclobuten-3-yl and 1-phenylallyl anions (1a and 2a, respectively) were prepared in the gas phase by deprotonating their conjugate acids in a Fourier transform mass spectrometer. The acidities of both compounds were measured by determining equilibrium constants with standard reference acids [G°acid(1) = 369.5 ? 0.7 kcal mol^-1 and H°acid(1) = 377.5 ? 0.7 kcal mol^-1 ; G°acid(2) = 361.5 ? 2.1 kcal mol^-1 and H°acid(2) = 368.1 ? 2.1 kcal mol^-1]. Electron affinities of the corresponding radicals were measured by the bracketing technique [EA = 0.94 ? 0.11 (1r) and 1.06 ? 0.07 eV (2r)] and allylic C?H bond dissociation energies were obtained via a thermodynamic cycle [BDE = 85.6 ? 2.6 (1) and 78.9 ? 2.6 (2) kcal mol^-1]. These results are contrasted to density functional theory and ab initio calculations on cyclobutene, 1-phenylcyclobutene, (E)-1-phenylpropene and propene.

Multiple aminopropyl substitutions of the initial N,N′,N″-trimethylguanidine lead to high intrinsic absolute proton affinities (APA) and basicities culminating in APA = 268.4 kcal mol−1 (1 kcal = 4.184 kJ) in N,N′,N″-tris(3-aminopropyl)guanidine (9). The reason behind a high proton affinity is identified as a strong cationic resonance in the central guanidine moiety and the strength of the intramolecular hydrogen bonding (IMHB), which is enhanced upon protonation. A cooperative IMHB effect in 9 and 9H+ realized by three N(sp3)H···N(sp3) H-bridges is estimated to be as high as 14.7 and 33.0 kcal mol−1, respectively. It follows that the IMHB effect contributes 18.3 kcal mol−1 to the absolute proton affinity of 9, which is a respectable amount. The basicity of 9 in acetonitrile is estimated to be very high, as evidenced by the corresponding pKa = 28.8. A derivative of 9, N,N′,N″-tris(3-dimethylaminopropyl)guani-dine (10), assumes an even higher superbasic proton affinity of 275 kcal mol−1 due to an additional relaxation effect caused by the methyl groups. The corresponding pKa(MeCN) = 29.4. Copyright © 2002 John Wiley & Sons, Ltd.

The basicity of a family of 2,5-dihydropyrrolimines is examined by the Hartree-Fock model. It is found that these systems exhibit high proton affinity, which increases with the number of the five-membered rings present. The origin of the pronounced basicity is identified as the tandem or domino aromatic effect occurring in the conjugate acids. The aromatization is triggered by protonation and spread over whole systems via mobile π-electrons. Proton affinities as high as 300 kcal/mol or more can be achieved in the gas phase, if the aromatization is combined with the favourable substituent effects and with the intramolecular hydrogen bond corona effect. Copyright © 2002 John Wiley & Sons, Ltd.

Various methods such as high speed vibrational milling, high pressure, ultrasound, microwave irradiation, and conventional heating conditions are employed for the reaction of tetramethylguanidine with carbodiimides.

Three series of novel trisubstituted guanidines containing at least one hydrogen bond accepting (HBA) group were modelled using B3LYP/6–311+G(2df,p)//B3LYP/6–31G(d) calculations. Their structure was modified by incorporating a variety of different HBA groups covering a wide range of hydrogen bond strengths. Calculated gas-phase basicities (GBs) ranged from 1035 to 1181 kJ mol–1 depending on the nature of the substituent. To rationalise changes in the GB, a correlation of GB against two independent variables (pKHB and σ4B) was conducted where pKHB served as the descriptor of the hydrogen bond strength and σ4B was introduced to describe changes in the GBs in the open-chain model systems, i.e. in the absence of intramolecular hydrogen bond (IMHB), caused by the electronic effect of the propyl-HBA substituent. A very good correlation of the calculated gas-phase basicities against these two independent variables was established for all three sets of the bases.

Chiral amino acid- and amino alcohol-oxalamides are well-known as versatile and efficient gelators of various lipophilic and polar organic solvents and water. To further explore the capacity of the amino acid/oxalamide structural fragment as a gelation-generating motif, the dioxalamide dimethyl esters 1(6)Me and 1(9)Me, and dicarboxylic acid 2(6)OH/2(9)OH derivatives containing flexible methylene bridges with odd (9; n=7) and even (6; n=4) numbers of methylene groups were prepared. Their self-assembly motifs and gelation properties were studied by using a number of methods (FTIR, (1)H NMR spectroscopy, CD, TEM, DSC, XRPD, molecular modeling, MMFF94, and DFT). In contrast to the previously studied chiral bis(amino acid or amino alcohol) oxalamide gelators, in which no chiral morphology was ever observed in the gels, the conformationally more flexible 1(6)Me, 1(9)Me, 2(6)OH, and 2(9)OH provide gelators that are capable of forming diverse aggregates of achiral and chiral morphologies, such as helical fibers, twisted tapes, nanotubules, straight fibers, and tapes, in some cases coexisting in the same gel sample. It is shown that the differential scanning calorimetry (DSC)-determined gelation enthalpies could not be correlated with gelator and solvent clogP values. Spectroscopic results show that intermolecular hydrogen-bonding between the oxalamide units provides the major and self-assembly directing intermolecular interaction in the aggregates. Molecular modeling studies reveal that molecular flexibility of gelators due to the presence of the polymethylene bridges gives three conformations (zz, p1, and p2) close in energy, which could form oxalamide hydrogen-bonded layers. The aggregates of the p1 and p2 conformations tend to twist due to steric repulsion between neighboring iBu groups at chiral centers. The X-ray powder diffraction (XRPD) results of 1(6)Me and 1(9)Me, xerogels prove the formation of p1 and p2 gel aggregates, respectively. The latter results explain the formation of gel aggregates with chiral morphology and also the simultaneous presence of aggregates of diverse morphology in the same gel system.

One-pot synthesis of new pentasubstituted triguanides 1a–e starting from the corresponding monosubstituted guanidine derivatives and diisopropylcarbodiimide is described and a mechanism for formation of the products observed is proposed. The structures of 1a–d were elucidated by spectroscopic analyses of their acetate salts. The structure of compound 1e was also confirmed by X-ray crystallography using its sulfate salt. The X-ray structure provided strong evidence of extensive electron delocalization within the triguanide core despite its non-planar structure. In addition, the effect of tautomerism on the course of the reaction, with emphasis on possible reaction paths leading to the side products, is discussed in some detail. Finally, antiproliferative effects of the acetate salts of the newly prepared compounds on five cancer lines in vitro were evaluated. It was found that acetates of 1a–c exhibit strong cytostatic and cytotoxic activity, with the strongest effect observed for the acetate of benzyl derivative 1c.

We report a new solid-state photochemical rearrangement by which aromatic N-chloroamides exposed to UV light or sunlight are rapidly and efficiently converted to chloroaromatic amides in the crystalline state. The course, the intermediate (nascent chlorine vs. dichlorine) and the outcome of the reaction depend on the excitation (exposure time, wavelength and intensity) and on inherent structural factors (the directing role of the substituents and, as demonstrated by the different reactivity of two polymorphs of N-chlorobenzanilide, the supramolecular structure). The photolysis of the chloroamides provides facile photochemical access to arylamidyl radical intermediates, which in the absence of strong hydrogen bond donors are stabilized in the reactant crystals by C―H/N―Cl---pi interactions, thus providing insight into their structure and chemistry. Thorough theoretical modeling of the factors determinant to the stability and the nature of the spin-hosting orbital evidenced that although the trans-PI_|| state (Np spin) of the amidyls is normally preferred over the trans-SIGMA configuration (Nsp2 spin), stabilization by aromatic conjugation, steric and geometry factors, as well as by electronic effects from the substituents can decrease the PI―SIGMA gap in these intermediates significantly, resulting in similar and, in the case of the orthogonal amide-phenyl disposition―even reversed population of the unpaired electron in the two orbitals. Quantitative correlation established that the inverted spin stability and the PI_N―SIGMA_N crossover are collectively facilitated by the conformation, valence angle and disposition of the amide group relative to the aromatic system. The stabilization and detection of a trans-SIGMA radical was experimentally accomplished by steric locking of the orthogonal trans amide conformation with double ortho-tert-butyl substitution at the phenyl ring. The effects of the single para-phenyl substituents on the relative occupational stability of the arylamidyl radical states points out to non-Hammett behavior of the aromatic amidyl radicals. By including cumulative electronic effects from multiple substitutions, four distinct families of these species were identified. The PI state is the most stable structure of the N-phenylacetamidyl radical and of most of the substituted radicals, although the SIGMA and PI states can be also stabilized by introducing tert-butyl and nitro groups, respectively.

The coordination chemistry of nickel(II) nitrate with four guanidines bearing heteroatom-containing alkyl sidechains is investigated by means of electrospray ionization mass spectrometry of dilute methanolic solutions. In contrast to other nitrogen bases, the ESI spectra of the solutions containing superbasic guanidines are dominated by signals due to the protonated nitrogen bases, BH + . Under soft ionization conditions, also several nickel-containing ions are observed which are best described as complexes between the guanidinum ions BH + with neutral nickel(II) nitrate coordinated via the nitrato ligands in terms of ion pairs. For guanidine derivatives with at least two N , N- dimethylaminopropyl groups in the sidechains, also the formation of genuine amino-nickel complexes is inferred. The pronounced difference between the ions formed upon ESI of aqueous nickel(II) nitrate in the presence of guanidines compared to other, weaker nitrogen bases is ascribed to the high basicity of the guanidines, which renders their protonation much more favored than their possible operation as ligands for the metal center.

A series of cis-pyramidalized disilenes was modeled by ab initio and DFT methods with the special emphasis on character of the wavefunction. Spin restricted DFT (RDFT) and MP2 approaches predicted qualitatively different structures of disilenes as the minima (deformed zwitterionic and symmetrical diradicaloid, respectively). Additional CASSCF and broken symmetry spin unrestricted DFT (BS-UDFT) calculations confirmed symmetrical structures as more reliable minimum. The only exception is highly strained 1, 4-disilabicyclo[2.2.0]hex-1, 4-ene where deformed zwitterionic structure is corroborated by most of the applied methods including high-level MR-AQCC calculation. Analysis of the wavefunction obtained for both deformed and symmetrical minima indicates a strong tendency of the RDFT method to prefer structures possessing a closed shell wavefunction even though a strong electron density shift occurs. The results obtained at CASSCF level of theory showed that for a correct description of geometries of such systems, a two-configurational wavefunction is needed at least. The BS-UDFT and spin restricted MP2 methods describe such “ diradicaloid” geometries of cis-pyramidalized disilenes qualitatively correct although from different reasons.

The basicities of a large number of organic bases and superbases, including nitrogen basic centers in various chemical environments occurring in phosphazenes, amidines, amines, anilines and pyridines, have been studied in acetonitrile by the isodensity polarized continuum model employing two DFT computational schemes differing in the basis sets for final single-point calculations. It turned out that the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) method serves the purpose giving good agreement for basicities with experiment for both gas phase and acetonitrile solutions treating widely different bonding situations of basic nitrogen atoms on an equal footing. An attempt is made to correlate the experimental pKa(MeCN) values with the proton affinities (PA) in MeCN. The results are less accurate than those achieved by using basicities in acetonitrile. In particular, the PA(MeCN)s frequently failed in reproducing the pKa(MeCN) values in systems possessing multiple intramolecular hydrogen (IMH) bonds formed via corona effects. In such cases the use of basicities is mandatory instead. A useful corollary of these calculations on systems with multiple IMH bonds is that comparison of the theoretical and experimental pKa values can provide an insight into the structure of the most stable conformations in solutions.

Para-bisguanidinyl benzene 1 and its N-permethylated derivative 2 are both sufficiently strong bases to afford not only the monocations [1+H]+ and [2+H]+, but also the doubly protonated ions, [1+2H]2+ and [2+2H]2+, in the gas phase. The title ions generated via electrospray ionization are probed by collision-induced dissociation experiments which inter alia reveal that the dicationic species [1+2H]2+ and [2+2H]2+ can even undergo fragmentation reactions with maintenance of the 2-fold charge. Complementary results from density functional theory predict PAs above 1000 kJ mol(-1) for the neutral compounds, i.e., PA(1) = 1025 kJ mol(-1) and PA(2) = 1067 kJ mol(-1). Due to the stabilization of the positive charge in the guanidinium ions and the para-phenylene spacer separating the basic sites, even the monocations bear sizable proton affinities, i.e., PA([1+H]+) = 740 kJ mol(-1) and PA([2+H]+) = 816 kJ mol(-1).

The pKa values of seven novel guanidine derivatives, six of them possessing heteroalkyl substituents capable of forming intramolecular hydrogen bonds, were determined in acetonitrile (MeCN) by using the UV/Vis spectrophotometric titration method. The obtained pKa values range from 24.7 to 27.2. The most basic among the studied guanidines was found to be by ca. 4 pKa units more basic than thewell-known superbase N1,N1,N3,N3-tetramethylguanidine (TMG). The trends in the changes in the measured pKa values were compared with the experimental (determined by the extended kinetic method) and theoretical [B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d)] gas-phase proton affinities. It was shown that basicity ordering of the bases with dimethylaminopropyl substituents in acetonitrile follows the trend encountered in the gas phase. However, this is not the case for the methoxypropyl-substituted guanidines indicating that in these molecules formation of the intramolecular hydrogen bonds is to large extent hindered due to solvation by acetonitrile.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The gas-phase proton affinities (PAs) of four novel guanidine derivatives, with three of them incorporating heteroalkyl groups capable of forming intramolecular hydrogen bonds, are determined by the extended kinetic method. In addition, the PAs of two other guanidines are evaluated using the simple variant of the kinetic method. The proton affinities of the investigated bases fall in the range of 251–264 kcal mol −1 and are thus 16–29 kcal mol −1 larger than the proton affinity of the parent compound guanidine. It is shown that the formation of intramolecular hydrogen bonds, where possible, significantly contributes to the basicity of the guanidine bases under study.

The synthesis of novel N, N', N'' tris(3 dimethylaminopropyl)-guanidine 1 is described and the X-ray structure of its hexafluorophosphate salt measured (1H· PF6). The hydrogen bonding in protonated 1 and in 1H· PF6 is also discussed.

DFT calculations of 7'-oxasesquinorbornenes and 7, 7'-dioxasesquinorbornenes using the B3LYP/6-31G* method are reported. All the investigated structures (syn- and anti- derivatives) showed significant non-planarity of the central double bond, with the exception of those anti-derivatives possessing symmetrical structures. The influence of the replacement of the methylene groups at position 7- of the norbornene fragment with oxygen and the introduction of second and third (peripheral) double bonds and benzene rings on the molecular and electronic structures of these molecules have also been investigated.

MP2 and DFT calculations employing 6-31G* were carried out to investigate the structure of some of the carbocations and their boron analogues embedded in the syn-sesquinorbornene framework, hitherto not observed experimentally. The calculated minimum energy structures of all species provide evidence for homoconjugative interaction between the electron deficient center(s) and the carbon?carbon double bond. The use of isodesmic reactions based upon MP2(fc)/6-31G* energies indicates that the homoconjugative stabilisation of mono- and di-cations is greater than those of the isoelectronic boron compounds. The calculated 13 C and 11 B NMR chemical shifts support this conclusion.