Benzhydryl Derivatives Research Articles

One-Carbon Homologation of Knoevenagel Adducts: Enantioselective Access to Benzhydryl Derivatives.

A one-carbon homologation of Knoevenagel adducts enabling the insertion of a CHAr fragment is reported. The strategy involves a sulfur ylide mediated cyclopropanation followed by the rearrangement of cyclopropanes and enables the synthesis of a series of benzhydryl derivatives. Mechanistic studies reveal that the cyclopropane rearrangement involves a Lewis acid catalyzed ring-opening followed by the 1,2-migration of an aryl group. The possibility of controlling the absolute stereochemistry of the generated stereogenic allylic carbon center using a chiral sulfonium ylide is demonstrated.

Arylation Using Sulfonamides: Phenylacetamide Synthesis through Tandem Acylation-Smiles Rearrangement.

A range of electron-poor and heterocyclic sulfonamides react with phenylacetyl chlorides to produce benzhydryl derivatives in a single step. The reaction proceeds via tandem amide bond formation/Dohmori-Smiles rearrangement under the simple conditions of an aqueous base. In the case of o-nosylamides, a further reaction takes place at the nitro group to yield indazoles.

Primaquine hybrids as promising antimycobacterial and antimalarial agents

Four series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k, ureas 2a-s, semicarbazides 3a-c and bis-ureas 4a-u. Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and compared with PQ and the standard antitubercular drugs. In general, the PQ derivatives showed higher potency than the parent compound. Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug ciprofloxacin, and weak or no activity against MTB and MAC. bis-Trifluoromethylated cinnamamide 1k showed low cytotoxicity and high activity against all three Mycobacterium species and their activities were comparable or slightly higher than those of the reference drugs. PQ urea derivatives with hydroxyl, halogen and trifluoromethyl substituents on benzene ring 2f-p exerted very strong antimycobacterial activity towards all tested mycobacteria, stronger than PQ and the relevant standard drug(s). Unfortunately, these compounds had relatively high cytotoxicity, except bromo 2l and trifluoromethyl 2m, 2n derivatives. In general, meta-substituted derivatives were more active than analogues para-derivatives. Phenyl ureas were also more active than cycloalkyl or hydroxyalkyl ureas. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. Bis-urea derivatives 4 were generally less active than the urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis-urea derivatives, only p-Cl/m-CF3 phenyl derivative 4p, benzhydryl derivatives 4t and 4u and bis-PQ derivative 4s showed high activity, higher than all three reference drugs. After comparison of activity and cytotoxicity, urea 2m and bis-urea 4u could be considered as the most promising agents. Antimalarial potential of PQ derivatives in vitro against the liver stage of P. berghei was evaluated as well. 3-(4-Chlorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea (4l) was the most active compound (IC50 = 42 nM; cytotoxicity/activity ratio >2000). Our results bring new insights into development of novel anti-TB and antimalarial compounds.

Impact of Electronic Effects on the Nucleofugality of Leaving Groups

A short review of the development of nucleofugality and electrofugality scales based on solvolysis rates of benzhydryl derivatives is presented. Accordingly, the rate of the heterolytic step in the SN1 displacement reaction and the leaving group ability (nucleofugality) in a given solvent are related with the special linear free-energy relationship (LFER) equation: log k = s f (N f + E f). The impact of electronic effects in the leaving group (nucleofuge) on the overall SN1 reactivity of the substrate is given. The importance of inductivity, resonance, polarity and field effects in the leaving group moiety in the transition state is analyzed. Also, the effect of the negative hyperconjugation and the influence of other electronic effects in the leaving group on the height of the reaction intrinsic barrier are considered.1 Introduction2 Development of the Nucleofugality Scale3 Inductive and Resonance Effects4 Negative Hyperconjugation5 Intrinsic Barrier6 Conclusions

Philicities, Fugalities, and Equilibrium Constants.

The mechanistic model of Organic Chemistry is based on relationships between rate and equilibrium constants. Thus, strong bases are generally considered to be good nucleophiles and poor nucleofuges. Exceptions to this rule have long been known, and the ability of iodide ions to catalyze nucleophilic substitutions, because they are good nucleophiles as well as good nucleofuges, is just a prominent example for exceptions from the general rule. In a reaction series, the Leffler-Hammond parameter α = δΔG(⧧)/δΔG° describes the fraction of the change in the Gibbs energy of reaction, which is reflected in the change of the Gibbs energy of activation. It has long been considered as a measure for the position of the transition state; thus, an α value close to 0 was associated with an early transition state, while an α value close to 1 was considered to be indicative of a late transition state. Bordwell's observation in 1969 that substituent variation in phenylnitromethanes has a larger effect on the rates of deprotonation than on the corresponding equilibrium constants (nitroalkane anomaly) triggered the breakdown of this interpretation. In the past, most systematic investigations of the relationships between rates and equilibria of organic reactions have dealt with proton transfer reactions, because only for few other reaction series complementary kinetic and thermodynamic data have been available. In this Account we report on a more general investigation of the relationships between Lewis basicities, nucleophilicities, and nucleofugalities as well as between Lewis acidities, electrophilicities, and electrofugalities. Definitions of these terms are summarized, and it is suggested to replace the hybrid terms "kinetic basicity" and "kinetic acidity" by "protophilicity" and "protofugality", respectively; in this way, the terms "acidity" and "basicity" are exclusively assigned to thermodynamic properties, while "philicity" and "fugality" refer to kinetics. Benzhydrylium ions (diarylcarbenium ions) with para- and meta-substituents are used as reference compounds for these investigations, because their Lewis acidities and electrophilicities can be varied by many orders of magnitude, while the steric surroundings of the reaction centers are kept constant. The rate constants for their reactions with nucleophiles correlate linearly over a wide range with the Lewis acidities of the benzhydrylium ions: from slow reactions with late transition states to very fast reactions with early, reactant-like transition states (including reactions which proceed without an enthalpic barrier, ΔH(⧧) = 0). Thus, unequivocal evidence is obtained that even within a series of closely related reactions, the Leffler-Hammond α cannot be a measure for the position of the transition state. Differences in intrinsic barriers lead to deviations from the linear rate-equilibrium correlations and give rise to counterintuitive phenomena. Thus, 1,4-diazabicyclo[2.2.2]octane (DABCO) reacts with lower intrinsic barriers than 4-(dimethylamino)pyridine (DMAP) and, therefore, is a stronger nucleophile as well as a better nucleofuge than DMAP. Common synthetically used SN2 reactions are presented, in which weak nucleophiles replace stronger ones. Whereas solvolysis rates of alkoxy- and alkyl-substituted benzhydryl derivatives correlate linearly with the Lewis acidities of the resulting carbenium ions, this is not the case for amino-substituted benzhydrylium ions, where differences in intrinsic barriers play a major role. The common rule that a structural variation, which increases the electrophilicity of a carbocation at the same time reduces its electrofugality, does not hold any longer. The need to systematically analyze the role of intrinsic barriers is emphasized.

Nucleofugalities of Neutral Leaving Groups in 80 % Aqueous Acetonitrile

Nucleofugalites of tetrahydrothiophene, dimethyl sulfide and differently substituted pyridines in 80 % aqueous acetonitrile have been derived from the SN1 solvolysis rate constants of the corresponding X,Y-substituted benzhydryl derivatives (1–10). In sol-volysis of sulfonium ions in 80 % aqueous acetonitrile, where acetonitrile is a good cation solvator, the solvation of the reactant ground state is an important rate determining variable since the positive charge is almost entirely located on the leaving group. As a consequence, reaction rates of sulfonium ions are more sensitive to the substrate structure in 80 % aqueous acetonitrile than in pure and aqueous alcohols, which are less efficient as cation solvators. In solvolysis of pyridinium ions the solvation of the reactant ground state is less important, since the positive charge is considerably distributed between the carbon at the reaction center and the leaving group. In such cases the important rate determining variable is solvation of the transition state. Slower reactions of pyridinium sub-strates progress over later, carbocation-like transition states in which the solvation is more important, so those substrates solvolyze slightly faster in aqueous acetonitrile than in methanol (k80AN > kM). Faster reactions proceed over earlier TS in which the solvation is diminished, so those substrates solvolyze somewhat faster in methanol than in aqueous acetonitrile (k80AN < kM). This work is licensed under a Creative Commons Attribution 4.0 International License.

Facile New Syntheses of Substituted Benzhydryl Derivatives Using Trichloroacetimidate C-C Bond Formation Method

An improved syntheses of substituted benzhydryl derivatives has been developed. This facile two-step procedure involves C-C bond formation from O-diphenylmethyltrichloroacetimidate and C-nucleophiles in the presence of TMSOTf. The C-nucleophiles include arenes, alkenes, alkene silylated C-nucleophiles and trimethylsiloxy alkenes to give a series substituted benzhydryl derivatives in excellent yields.

Ion‐Pairing of Phosphonium Salts in Solution: CH⋅⋅⋅Halogen and CH⋅⋅⋅π Hydrogen Bonds

The (1) H NMR chemical shifts of the C(α)H protons of arylmethyl triphenylphosphonium ions in CD2 Cl2 solution strongly depend on the counteranions X(-) . The values for the benzhydryl derivatives Ph2 CHPPh3 (+) X(-) , for example, range from δH =8.25 (X(-) =Cl(-) ) over 6.23 (X(-) =BF4 (-) ) to 5.72 ppm (X(-) =BPh4 (-) ). Similar, albeit weaker, counterion-induced shifts are observed for the ortho-protons of all aryl groups. Concentration-dependent NMR studies show that the large shifts result from the deshielding of the protons by the anions, which decreases in the order Cl(-) > Br(-) ≫ BF4 (-) > SbF6 (-) . For the less bulky derivatives PhCH2 PPh3 (+) X(-) , we also find CH⋅⋅⋅Ph interactions between C(α)H and a phenyl group of the BPh4 (-) anion, which result in upfield NMR chemical shifts of the C(α)H protons. These interactions could also be observed in crystals of (p-CF3 -C6 H4 )CH2 PPh3 (+) BPh4 (-) . However, the dominant effects causing the counterion-induced shifts in the NMR spectra are the CH⋅⋅⋅X(-) hydrogen bonds between the phosphonium ion and anions, in particular Cl(-) or Br(-) . This observation contradicts earlier interpretations which assigned these shifts predominantly to the ring current of the BPh4 (-) anions. The concentration dependence of the (1) H NMR chemical shifts allowed us to determine the dissociation constants of the phosphonium salts in CD2 Cl2 solution. The cation-anion interactions increase with the acidity of the C(α)H protons and the basicity of the anion. The existence of CH⋅⋅⋅X(-) hydrogen bonds between the cations and anions is confirmed by quantum chemical calculations of the ion pair structures, as well as by X-ray analyses of the crystals. The IR spectra of the Cl(-) and Br(-) salts in CD2 Cl2 solution show strong red-shifts of the CH stretch bands. The CH stretch bands of the tetrafluoroborate salt PhCH2 PPh3 (+) BF4 (-) in CD2 Cl2 , however, show a blue-shift compared to the corresponding BPh4 (-) salt.

ChemInform Abstract: Effect of the Leaving Group and Solvent Combination on the LFER Reaction Constants

AbstractReview: 43 refs.

Effect of the Leaving Group and Solvent Combination on the LFER Reaction Constants

Fine effects that influence the variations of the reaction constants sf in LFER log k = sf(Nf + Ef) have been summarized here. Increasing solvent polarity in the series of binary mixtures increases the solvolysis rates for the same factor for all benzhydryl derivatives in which the solvation of the leaving group moiety in the transition state is substantial, i.e., log k vs. Ef correlation lines are parallel (same sf). For the substrates in which the demand for solvation of the leaving groups moiety is reduced, (e.g., carbonates) sf parameters decrease as the fraction of the water in a given solvent/water mixture increases (log k vs. Ef plots converge), due to decreasing solvation of the electrofuge moiety toward bigger electrofugality. The abscissa of the intersection of the converging plots might indicate the critical electrofugality above which the solvolysis rates should not depend of the water fraction. Larger reaction constant sf indicate later transition state for structurally related substrates only, while sf parameters for structurally different substrates cannot be compared likely due to different intrinsic barriers. Inversion in relative abilities of leaving groups is possible if they have similar reactivities and are characterized with different reaction constants.

A Practical Guide for Estimating Rates of Heterolysis Reactions

Chemists are well trained to recognize what controls relative reactivities within a series of compounds. Thus, it is well-known how the rate of ionization of R-X is affected by the stabilization of the carbocation R(+), the nature of the leaving group X(-), or the solvent ionizing power. On the other hand, when asked to estimate the half-life of the ionization of a certain substrate in a certain solvent, most chemists resign. This question, however, is crucial in daily laboratory practice. Can a certain substrate R-X be handled in alcoholic or aqueous solution without being solvolyzed? Can a biologically active tertiary amine or azole be released by ionization of a quaternary ammonium ion? In this Account, we describe a straightforward means of addressing such experimental concerns. A semiquantitative answer to these questions is given by the correlation equation log k(25 °C) = s(f)(N(f) + E(f)), in which carbocations R(+) are characterized by the electrofugality parameter E(f), and leaving groups X(-) in a certain solvent are characterized by the nucleofugality parameter N(f) and the nucleofuge-specific sensitivity parameter s(f). As s(f) is typically around 1 (0.8 < s(f) < 1.2), ionization half-lives of around 1 h at 25 °C can be expected when E(f) + N(f) = -4. This correlation equation is formally analogous to the linear free energy relationship that was used to derive the most comprehensive nucleophilicity and electrophilicity scales presently available (Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles. J. Am. Chem. Soc. 2001, 123, 9500-9512). By subjecting 628 solvolysis rate constants k(25 °C) for different benzhydryl derivatives (aryl(2)CH-X) to a least-squares minimization on the basis of the correlation equation, we obtained and tabulate here (i) the electrofugality parameters E(f) for 39 benzhydrylium ions and (ii) the nucleofuge-specific parameters N(f) and s(f) for 101 combinations of common leaving groups and solvents. We show that the E(f) parameters of the reference electrofuges can be used to determine N(f) and s(f) for almost any combination of leaving group and solvent. The nucleofuge-specific parameters of the reference systems can analogously be used to derive the electrofugalities E(f) of other types of carbocations. While it has long been recognized that good nucleophiles are not necessarily poor nucleofuges, it is now reported that there is also no general inverse relationship between electrophilicity and electrofugality. Although more electrophilic methyl- and methoxy-substituted benzhydrylium ions are generally weaker electrofuges, the inverse relationship between electrophilicity and electrofugality breaks down in the series of amino-substituted benzhydrylium ions. Because neither differential solvation of the carbocations nor steric effects are explicitly considered by this treatment, predictions for substrates not belonging to the benzhydrylium series are only reliable within a factor of 10. This is hardly acceptable to physical organic chemists, who are used to high precision within narrow groups of compounds. The synthetic chemist, however, who is seeking orientation in a reactivity range of 25 orders of magnitude, might appreciate the simplicity of this approach, which only requires considering the sum E(f) + N(f) or consulting our summary graphs.

Kinetics of the Solvolyses of Fluoro‐Substituted Benzhydryl Derivatives: Reference Electrofuges for the Development of a Comprehensive Nucleofugality Scale

AbstractA series of m‐fluoro‐substituted benzhydryl chlorides, bromides, mesylates, and tosylates 1‐X to 5‐X were prepared and subjected to solvolysis reactions in various solvents. The observed first‐order rate constants ks(25 °C) were found to follow the correlation equation log ks(25 °C) = sf(Nf + Ef), which allowed us to determine the electrofugality parameters Ef for these destabilized benzhydrylium cations and the nucleofugality parameters Nf, sf for a series of leaving group/solvent combinations.

Effect of the leaving group solvation on solvolytic behavior of benzhydryl derivatives

AbstractAn effect of the leaving group (LG) solvation on reactivity of benzhydryl derivatives in SN1 reactions has been investigated by using X,Y‐substituted benzhydryl phenyl carbonates, methyl carbonates, 3,5‐dinitrobenzoates (DNB), and the corresponding benzhydryl chlorides as reference compounds. Reaction constants (sf) derived from LFER equation log k (25 °C) = sf(Nf + Ef) indicate that sf parameters of carbonates and DNBs decrease as the fraction of the water in a given solvent/water mixture increases, while those of chlorides remain unchanged. This phenomenon is due to less important solvation and less charge separation in the TS. Effects of the solvents on the reaction rates were analyzed by Grunwald–Winstein correlations using various solvent‐ionizing power scales. The m values obtained for carbonates and DNBs are considerably smaller than the m values for chlorides. Also, the solvolysis rate constants of substrates that have stronger electrofuges are less influenced by solvent (lower m) than those with weaker electrofuges. Values of m parameters obtained for a given substrate in a given binary solvent system correlate well with the electrofugality of the generated benzhydrylium ion. Abscissa at which m = 0 represents the extrapolated critical electrofugality E of the substrates whose solvolysis rates should not depend on the water fraction in the aqueous/organic solvent mixtures. Similar values for the critical electrofugality have also been obtained from extrapolated logk versus Ef plots. Copyright © 2009 John Wiley &amp; Sons, Ltd.

Photosensitized electron transfer oxidation of sulfides: structure and medium effect

Oxidation of a series of sulfides R′ SR (R′,dodecyl,phenethyl,benzyl,cumyl,benzhydryl; R,ethyl,phenyl) under photoinduced electron transfer conditions (sensitizers: 9,10-dicyanoanthracene,triphenylpyrylium tetrafluoroborate) yields sulfoxides,products of trapping of the alkyl cation (for the benzhydryl and cumyl derivatives),and mainly aldehydes or ketones that result from α -deprotonation. The competing paths from the sulfide radical cation are discussed in this paper.

Electrofugality index for benzhydryl derivatives

We propose and test an empirical electrofugality index to rank the leaving group ability of a series of 21 benzhydryl derivatives. The empirical model defines the electrofugality as the negative of the global electrophilicity of the carbocation intermediate in the hydrolysis reaction. The results are in good agreement with the experimental electrofugality scale proposed for the title compounds by Mayr and coworkers [B. Denegri, A. Streiter, S. Júric, A.R. Ofial, O. Kronja, H. Mayr, Chem. Eur. J. 12 (2006) 1648].

Kinetics of the Solvolyses of Benzhydryl Derivatives: Basis for the Construction of a Comprehensive Nucleofugality Scale

In the paper by H. Mayr et al., the last row of data and footnotes of Table 1 are missing from page 1653 and should have appeared as shown below. Although the html data for this paper is complete and correct, an error was introduced into the pdf file during the final typesetting process. The editorial office apologizes for this omission and is grateful to the author for alerting us to it. Nucleofuge Electrofuge ks [s−1] kcalcd [s−1][a] Ref. Leaving group Solvent[b] X, Y Cl TFE[f] 4-NO2 5.44×10−5 [e] (8.87×10−4) [24] 3-Cl, 3′-Cl 7.20×10−4 4.38×10−4 – 3,5-(Cl)2, 3′-Cl 1.39×10−5 1.71×10−5 –

Kinetics of the Solvolyses of Benzhydryl Derivatives: Basis for the Construction of a Comprehensive Nucleofugality Scale

A series of 21 benzhydrylium ions (diarylmethylium ions) are proposed as reference electrofuges for the development of a general nucleofugality scale, where nucleofugality refers to a combination of leaving group and solvent. A total of 167 solvolysis rate constants of benzhydrylium tosylates, bromides, chlorides, trifluoroacetates, 3,5-dinitrobenzoates, and 4-nitrobenzoates, two-thirds of which have been determined during this work, were subjected to a least-squares fit according to the correlation equation log k(25 degrees C) = sf(Nf + Ef), where sf and Nf are nucleofuge-specific parameters and Ef is an electrofuge-specific parameter. Although nucleofuges and electrofuges characterized in this way cover more than 12 orders of magnitude, a single set of the parameters, namely sf, Nf, and Ef, is sufficient to calculate the solvolysis rate constants at 25 degrees C with an accuracy of +/-16 %. Because sf approximately 1 for all nucleofuges, that is, leaving group/solvent combinations, studied so far, qualitative discussions of nucleofugality can be based on Nf.

Palladium-catalyzed insertion reactions of trimethylsilyldiazomethane

Palladium(II) salts catalyze the Kirmse reaction of allylsulfides with trimethylsilyldiazomethane (TMSD) to give homoallylsulfides. Similarly, TMSD can intercept ArPdX intermediates generated during Stille couplings to give benzhydryl derivatives. The yields of this process are limited by overinsertion and β-elimination. Insertion and elimination can be harnessed to generate styrenes from benzylic halides in the presence of palladium (0) catalysts. Palladium can catalyze the Kirmse reaction of allylic sulfides, carbenoid insertion between Stille coupling partners and homologation of benzyl halides to give styrene derivatives.

Solvolyses of ferrocenylmethyl and .alpha.-ferrocenylethyl acetates: a YOAc solvent ionizing power scale

The solvolysis of ferrocenylmethyl acetate has been studied in 2,2,2-trifluoroethanol (TFE)-ethanol mixtures and in aqueous ethanol, acetone, and TFE; a Y OAc solvent ionizing power scale is developed. For 19 solvents, a fair correction with Y OTs values is obtained (slope of 0.88±0,08, correlation coefficient of 0.930); lateral dispersion is observed between excellent acetone-water, ethanol-water, and TFE-ethanol plots. In aqueous ethanol, the product partitioning is almost identical to that previously observed for benzhydryl derivatives

Synthesis and Ca-antagonist activity of some benzhydryl derivatives.

The preparation of a series of benzhydryl derivatives is described. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guinea-pig. These new compounds show lower activities as Ca-antagonists than Cinnarizine.