Showing papers on "Substituent published in 1991"

A survey of Hammett substituent constants and resonance and field parameters

Abstract: The Hammett equation (and its extended forms) has been one of the most widely used means for the study and interpretation of organic reactions and their mechanisms. Although the Hammett methodology has been criticized by theoreticians because of its empirical foundation, it is astonishing that u constants, obtained simply from the ionization of organic acids in solution, can frequently predict successfully equilibrium and rate constants for a variety of families of reactions in solution. Almost every kind of organic reaction has been treated via the Hammett equation, or its extended form. The literature is so voluminous and extensive that there is no complete review of all that has been accomplished. Hammett's success in treating the electronic effect of substituents on the rates and equilibria of organic reactions1P2 led Taft to apply the same principles to steric and inductive and resonance effects? Then, more recently, octanol/ water partition coefficients (P) have been used for rationalizing the hydrophobic effects of organic compounds interacting with biological systems? The use of log P (for whole molecules) or n (for substituents), when combined with electronic and steric parameters, has opened up whole new regions of biochemical and pharmacological reactions to study by the techniques of physical organic chemistry.sf3 The combination of electronic, steric, hydrophobic, hydrophilic, and hydrogen-bonding7 parameters has been used to derive quantitative structure-activity relationships (QSAR) for a host of interactions of organic compounds with living systems or parts thereof. The binding of organic compounds to proteins,8 their interaction with enzymess and with cellsloJ1 and tiasues,12 their inhibition of organelles,l' and as antimalarial^'^

Metal complex compounds

Abstract: A monocyclopentadienyl or substituted monocyclopentadienyl metal complex containing compound useful as a polymerization catalyst corresponding to the formula: CpMX.sub.n.sup.+ A.sup.- wherein: Cp is a single η 5 -cyclopentadienyl or η 5 -substituted cyclopentadienyl group optionally covalently bonded to M through a substituent; M is a metal of Group 3-10 or the Lanthanide Series of the Periodic Table bound in an η 5 bonding mode to the cyclopentadienyl or substituted cyclopentadienyl group; X each occurrence independently is selected from the group consisting of hydride, halo, alkyl, aryl, silyl, germyl, aryloxy, alkoxy, amide, siloxy, neutral Lewis base ligands and combinations thereof having up to 20 non-hydrogen atoms, and optionally one X together with Cp forms a metallocycle with M; R is alkyl or aryl of up to 10 carbons; n is one or two depending on the valence of M; and A is a noncoordinating, compatible anion of a Bronsted acid salt.

A Survey of Hammett Substituent Constants and Resonance and Field Parameters

Abstract: The Hammett equation (and its extended forms) has been one of the most widely used means for the study and interpretation of organic reactions and their mechanisms. Although the Hammett methodology has been criticized by theoreticians because of its empirical foundation, it is astonishing that u constants, obtained simply from the ionization of organic acids in solution, can frequently predict successfully equilibrium and rate constants for a variety of families of reactions in solution. Almost every kind of organic reaction has been treated via the Hammett equation, or its extended form. The literature is so voluminous and extensive that there is no complete review of all that has been accomplished. Hammett's success in treating the electronic effect of substituents on the rates and equilibria of organic reactions1P2 led Taft to apply the same principles to steric and inductive and resonance effects? Then, more recently, octanol/ water partition coefficients (P) have been used for rationalizing the hydrophobic effects of organic compounds interacting with biological systems? The use of log P (for whole molecules) or n (for substituents), when combined with electronic and steric parameters, has opened up whole new regions of biochemical and pharmacological reactions to study by the techniques of physical organic chemistry.sf3 The combination of electronic, steric, hydrophobic, hydrophilic, and hydrogen-bonding7 parameters has been used to derive quantitative structure-activity relationships (QSAR) for a host of interactions of organic compounds with living systems or parts thereof. The binding of organic compounds to proteins,8 their interaction with enzymess and with cellsloJ1 and tiasues,12 their inhibition of organelles,l' and as antimalarial^'^

Peptidyl (acyloxy)methyl ketones and the quiescent affinity label concept: the departing group as a variable structural element in the design of inactivators of cysteine proteinases

Abstract: (Acyloxy)methyl ketones, of general structure Z-[AA2]-[AA1]-CH2OCOAr, are potent inactivators of the cysteine proteinase cathepsin B. These reagents have been designed as affinity labels in which the dipeptidyl moiety serves as an affinity group (complementary to the S1 and S2 sites of the enzyme), while the (acyloxy)methyl ketone unit (-COCH2OCOR), containing a weak leaving group in the form of a carboxylate nucleofuge, functions as the potentially reactive entity that labels the enzyme. The inhibition is time dependent, active site directed, and irreversible. The apparent second-order rate constant kinact/Kinact, which characterizes the inhibition of cathepsin B by this series, spans several orders of magnitude and in certain cases exceeds 10(6) M-1 s-1. The activity of this series of inhibitors was found to be exquisitely sensitive to the nature of the carboxylate leaving group as well as the affinity group. A strong dependence of second-order inactivation rate on leaving group pKa was uncovered for Z-Phe-Ala (acyloxy)methyl ketones [log(k/K) = 1.1 (+/- 0.1) X pKa + 7.2 (+/- 0.4); r2 = 0.82, n = 26]. Heretofore in constructing affinity labels the choice of leaving group was quite restricted. The aryl carboxylate group thus offers considerable variation as a design element in that both its binding affinity and reactivity can be controlled by substituent effects. Specific peptidyl (acyloxy)methyl ketones thus represent prime examples of highly potent, chemically stable enzyme inhibitors with variable structural elements in both the affinity and departing groups.

Complexation of nucleotide bases by molecular tweezers with active site carboxylic acids: effects of microenvironment

Abstract: In chloroform-d molecular tweezer 1 forms a 1:l complex (Job plot) with 9-propyladenine (4). Changes in the UV-visible absorption spectrum of 1 upon addition of 4 and the changes 1 and 4 induce in each other's IH NMR spectrum are consistent with those of a complex comprised of hydrogen bonds and a-stacking interactions. The microenvironment around the carboxylic acid group in 1 markedly alters its complexation behavior relative to a simple carboxylic acid such as butyric acid (Lancelot, G. J. Am. Chem. SOC. 1977, 99,7037-7042). The association constants for the 1-4 and butyric acid-5 complexes are 25000 M-' (298 K) and 160 M-' (303 K), respectively. Butyric acid prefers a type 1 hydrogen bonding pattern while 1 adopts a type 7 pattern. The nucleotide base selectivities follow the order G > C > A > U for butyric acid and A > G >> C > U for 1. The presence of protic solvents markedly decreases the strength of the complex between 1 and 4. Two analogues of 1 have also been studied, molecular tweezer 2 and 3. Both lack the dimethylamino substituent found in 1, while 3 has a spacer unit that is fully oxidized. The association constants for the 2-4 and 3-4 complexes are 14000 and 120000 M-I, respectively.

New .alpha.-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity

Abstract: A series of new amino phosphonic acid derivatives of vinblastine (1, VLB) has been synthesized and tested in vitro and in vivo for antitumor activity. The compounds were obtained from O4-deacetyl-VLB azide. All of the new products studied were capable of inhibiting tubulin polymerization in vitro. The most potent antitumor compounds bore an alkyl substituent on the phosphonate. In these compounds, the anti-tumor activity strongly depended on the stereochemistry of the phosphonate. The phosphonate (1S)-[1-[( O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastin-3-yl] carbonyl]amino]-2-methylpropyl]phosphonic acid diethyl ester exhibited a remarkable activity against cancer cell lines both in vitro and in vivo.

Short, enantiogenic syntheses of (-)-indolizidine 167B and (+)-monomorine

Abstract: The enantiogenic syntheses of (−)-indolizidine 167B (1) and (+)-monomorine (2) are described. D-Norvaline and L-alanine are converted into their 1-pyrrole derivatives by reaction with 2,5-dimethoxytetrahydrofuran. Thereafter, Arndt-Eistert homologation of the N-alkanoic acid substituent, followed by rhodium (II) acetate catalyzed decomposition of its α-diazo ketone derivative, provides the relevant bicyclic precursors, the vested chirality of which directs catalytic hydrogenation affording 1 and 2. Provision for the 5-butyl side chain in 2 is made by prior Lewis acid catalyzed rearrangement of the mixed anhydride obtained from butyryl chloride and the pyrrole analogue of L-alanine

Glucose Analog Inhibitors of Glycogen-Phosphorylase - the Design of Potential-Drugs for Diabetes

Abstract: The T-state crystal structure of the glucose-phosphorylase b complex has been used as a model for the design of glucose analogue inhibitors that may be effective in the regulation of blood glucose levels. Modeling studies indicated room for additional atoms attached at the C1-beta position of glucose and some scope for additional atoms at the C1-alpha position. Kinetic parameters were determined for alpha-D-glucose: Ki = 1.7 mM, Hill coefficient n = 1.5, and alpha (synergism with caffeine) = 0.2. For beta-D-glucose, Ki = 7.4 mM, n = 1.5, and alpha = 0.4. More than 20 glucose analogues have been synthesized and tested in kinetic experiments. Most were less effective inhibitors than glucose itself and the best inhibitor was alpha-hydroxymethyl-1-deoxy-D-glucose (Ki = 1.5 mM, n = 1.3, alpha = 0.4). The binding of 14 glucose analogues to glycogen phosphorylase b in the crystal has been studied at 2.4-A resolution and the structure have been refined to crystallographic R values of less than 0.20. The kinetic and crystallographic studies have been combined to provide rationalizations for the apparent affinities of glucose and the analogues. The results show the discrimination against beta-D-glucose in favor of alpha-D-glucose is achieved by an additional hydrogen bond made in the alpha-glucose complex through water to a protein group and an unfavorable environment for a polar group in the beta pocket. The compound alpha-hydroxymethyl-1-deoxy-D-glucose has an affinity similar to that of glucose and makes a direct hydrogen bond to a protein group. Comparison of analogues with substituent atoms that have flexible geometry (e.g., 1-hydroxyethyl beta-D-glucoside) with those whose substituent atoms are more rigid (e.g., beta-azidomethyl-1-deoxyglucose or beta-cyanomethyl-1-deoxyglucose) indicates that although all three compounds make similar polar interactions with the enzyme, those with more rigid substituent groups are better inhibitors. In another example, alpha-azidomethyl-1-deoxyglucose was a poor inhibitor. In the crystal structure the compound made several favorable interactions with the enzyme but bound in an unfavorable conformation, thus providing an explanation for its poor inhibition. Attempts to utilize a contact to a buried aspartate group were partially successful for a number of compounds (beta-aminoethyl, beta-mesylate, and beta-azidomethyl analogues). The beta pocket was shown to bind gentiobiose (6-O-beta-D-glucopyranosyl-D-glucose), indicating scope for binding of larger side groups for future studies.

4.5 – Additions to N-Acyliminium Ions

Abstract: The addition of strongly polarized carbon-carbon double bonds (enols) to simple iminium ions, known as the Mannich reaction (equation 1), is a fundamentally important route to amines, especially in biosynthetic processes.1,2 This reaction type is less synthetically useful if weakly polarized or unpolarized carbon-carbon π-bonds are used as nucleophiles (equation 2).3 Because of the low electrophilic reactivity of the iminium moiety, the reverse reaction, known as the Grob fragmentation (equation 2), is often the more important process.4 However, if the iminium moiety has a carbonyl substituent on nitrogen, its electrophilicity is strongly enhanced, and reactions with CC bonds are irreversible and synthetically useful (equation 3).

Highly selective binding of simple peptides by a C3 macrotricyclic receptor

Abstract: We describe two chiral, C 3 -symmetric receptors having only limited conformational flexibility and deep basket-like binding sites These molecules bind diamides of certain amino acids with high selectivity which is dependent upon the nature of the amino acid side chain and the identity of the N-alkyl substituent

4.3 – Vinyl Substitutions with Organopalladium Intermediates

Abstract: Organopalladium halides, acetates, triflates and similar derivatives lacking β sp3-bonded hydrogens generally react easily with unhindered alkenes to form new alkenes in which an original, vinyl hydrogen is replaced by the organic group of the palladium reactant. The reactions occur in solution. Other Group VIII metals are ineffective in bringing about this transformation in acceptable yields. In the palladium reaction the organopalladium(II) reactant is reduced to the zero valent state while the halide, acetate, triflate or other, initial anionic ligand is converted into the corresponding acid (equation 1). If alkyl groups are attached directly to the double-bond carbons, double-bond rearrangement may occur and allylically substituted products can be produced. Normally, substitution occurs before any double-bond rearrangement occurs in the reactant alkene and the substituent is placed on one of the initial double-bond carbons (equation 2). Rearrangement of the double bond along a hydrocarbon chain to positions more distant from the substituent than the allylic position is occasionally observed, most often when X is a halogen and the halogen acid produced by the reaction is not neutralized as it is formed by inclusion of a base.

Fluorinated Liquid Crystals for Active Matrix Displays

Abstract: Eight types of two- and three-ring liquid-crystalline compounds each possessing a 3,4-difluorophenyl substituent were synthesized. Their liquid-crystalline mixtures were such as to make them useful for active matrix displays, such as TFT (thin-film-transistor) and MIM (metal-insuiator-metal) systems. They have high stability and low viscosity, very important properties so far not possible with conventional substances.

The Synthesis of Several Lateral Difluoro-substituted 4,4″-Dialkyl- and 4,4″-Alkoxyalkyl-Terphenyls and a Rationalisation of the Effect of Such Substitution on Mesophase Type and Transition Temperatures

Abstract: In recent years we have prepared a large number of mono-fluoro- and ortho-difluoro-substituted 4,4''-dialkyl- and 4,4''-alkoxyalkyl-terphenyls. The synthesis and transition temperatures of a variety of related difluoro compounds is presented here so that it is now possible to identify(i) broadening of the molecule, (ii) twisting about an inter-annular bond, and (iii) the presence of an inner (2-, 2'-, 3'- or 2'' substituent) or an outer (3- or 3''-substituent) fluorine, as being the major factors which influence the type and the thermal stability of the mesophases obtained

Photochemically induced radical cation diels-alder reaction of indole and electron-rich dienes

Abstract: Diels-Alder reactions between indole (3) and susbtituted cyclohexa-1,3-dienes (2) can be effected by a photoinduced catalyzed electron transfer reaction using catalytic amounts of triarylpyrylium tetrafluoroborates (1) as sensitizers and an acid chloride as a trapping agent. Irradiation generates N-acyl-1,4,4a,9a-tetrahydro-1,4-ethanocarbazoles in one step. The products are formed with nearly total regioselectivity, such that a substituent in the 1-position of the cyclohexa-1,3-diene is always found in the 1-position of the tetrahydrocarbazole, and a substituent in the 2-position of the diene always appears in the 3-position of the product

Analogs of the cyclic hydroxamic acid 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3-one (DIMBOA): decomposition to benzoxazolinones and reaction with .beta.-mercaptoethanol

Abstract: Analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-1,4-benzoxazin-3-ones) from Gramineae (Poaceae) have been synthesized by the reductive cyclization of the ring-substituted methyl α-(o-nitrophenoxy)-α-methoxyacetates, followed by demethylation of the C-2 methoxy group with BBr 3 or BCl 3 to reveal the 2-hydroxy group. A structure-activity series was produced by varying the substituent at C-7 on the aromatic ring [R=MeO, t-BU, Me, H, Cl, F, CO 2 Me]. The remarkable rate enhancement provided by an oxa functionality suggests that reduction occurs by direct attack of thiolate on the hydroxamic nitrogen of a resonance-stabilized ion pair

Methide salts, formulations, electrolytes and batteries formed therefrom

Abstract: Salts for use in nonaqueous electrolytes, and electrolytes and electrochemical generators including such materials. An exemplary compound for use as an electrolyte in an electrochemical cell has formula (I) wherein Mn+ is an ion of Li, Na, K, Ca, Mg, Zn, or Al; each of the moieties Y, Y', and Y'', are (a) or (b); the groups R and R' are separate halogenated alkyl groups of 1-4 carbon atoms, respectively or are joined together to constitute a unitary halogenated alkylene radical of from 2-4 carbon atoms linking Y and Y' and forming a ring structure which includes R, R', Y, Y', and the carbon atom to which Y and Y' are attached; the group R'' is an alkyl or haloalkyl radical of 1-4 carbon atoms or a halogenated phenyl group; n is an integer of 1-3 depending on the identity of the metal M; and metal ion Mn+ is an ion of Li, Na, Ca, Mg, Zn or Al when each of the Y-R, Y'-R', and Y''-R'' groups is SO?2?CF3. In another exemplary compound, the -Y''-R'' group is replaced by Z, which is an electron-withdrawing substituent selected from the group consisting of -C(O)H, -NO2, -CN, -F, and perfluorinated alkyls and aryls containing no more than 8 carbons.

Chemiluminescent 3--(Substituted adamant--2'--Ylidene) 1,2--Dioxetanes

Abstract: Enzymatically cleavable chemiluminescent 1,2-dioxetane compounds capable of producing light energy when decomposed, substantially stable at room temperature before a bond by which an enzymatically cleavable labile substituent thereof is intentionally cleaved, are disclosed These compounds can be represented by the formula: ##STR1## wherein: X and X 1 each represent, individually, hydrogen, a hydroxyl group, a halo substituent, an unsubstituted lower alkyl group, a hydroxy (lower) alkyl group, a halo (lower) alkyl group, a phenyl group, a halophenyl group, an alkoxyphenyl group, a hydroxyalkoxy group, a cyano group or an amide group, with at least one of X and X 1 being other than hydrogen; and R 1 and R 2 , individually or together, represent an organic substituent that does not interfere with the production of light when the dioxetane compound is enzymatically cleaved and that satisfies the valence of the dioxetane compound's 4-carbon atom, with the provisos that if R 1 and R 2 represent individual substituents the R 2 substituent is aromatic, heteroaromatic, or an unsaturated substituent in conjugation with an aromatic ring, and that at least one of R 1 and R 2 is, or R 1 and R 2 taken together are, an enzymatically cleavable labile group-substituted fluorescent chromophore group that produces a luminescent substance when the enzymatically cleavable labile substituent thereof is removed by an enzyme The corresponding dioxetanes which, instead of being substituted at the 5' or 7', or at the 5' and 7' positions, instead contain a 4' methylene group, are also disclosed, as are intermediates for all these 3-substituted adamant-2'-ylidenedioxetanes, and their use as reporter molecules in assays

Syntheses and properties of N-fluoropyridinium salts

Abstract: Various stable N-fluoropyridinium salts with a non- or weakly nucleophilic counter anion such as TfO−, FSO3−, BF4−, SbF6−, ClO4−, CH3SO3− etc., or with an electron-donating or -withdrawing substituent(s) on the pyridine ring were synthesized and their properties investigated. N-Fluoropyridinium-2-sulfonates, N-fluoroquinolinium triflate, and highly hindered N-fluoro-2,6-di-t-butylpyridinium salts were also synthesized. They were synthesized by counter anion displacement reactions of unstable pyridine-F2 compounds, fluorination of salts of pyridines with protonic acids or silyl esters with F2, and/ or fluorination of Lewis acid complexes of pyridines. The scope of each method was examined in detail. Each of the N-fluoropyridinium salts was assigned as the first stable 1 : 1 salt structure of the pyridine nucleus and halogen atom on the basis of the spectral and elemental analyses. The stability depended on the nucleophilicity or basicity of the counter anions and electronic nature or position of the ring s...

Electrochemical oxidation of proline derivatives : total syntheses of bulgecinine and bulgecin c

Abstract: The influence of structure on the efficiency of the electrochemical C-5 oxidation of (2S,4S)-hydroxyproline carbamate esters is presented. Optimum methoxylation was observed with (2S,4S)-4-acetoxy-1,2-pyrrolidine-dicarboxylic acid 2-methyl 1-(2-(trimethylsilyl)ethyl) etser (19). The corresponding C-5 methoxy derivative 20 was converted into bulgecinine (4) via a stereospecific radical homologation to incorporate the C-5 hydroxymethyl substituent. Bulgecin C (1a) was prepared via a β-stereoselective glycosidation reaction using a 2-azido-2-deoxy-α-D-glucopyranosyl trichloroacetimidate derivative, regiospecific C-4' sulfation, and deprotection

Similarity models in organic chemistry, biochemistry, and related fields

Abstract: 1. Similarity models: statistical tools and problems in using them (T.M. Krygowski and K. Wozniak). 2. Substituent effect parameters and models applied in organic chemistry (J. Shorter). 3. The transmission of substituent effects in organic systems (M. Godfrey). 4. Properties of hydrogen as a substituent in planar organic pi-systems (G. Hafelinger). 5. Similarity models in IR and UV spectroscopy (C. Laurence). 6. Description of properties of binary solvent mixtures (H. Langhals). 7. Additivity rules and correlation methods in gas chromatography (J. Oszczapowicz). 8. Similarity models in organic electrochemistry (J.S. Jaworski and M.K. Kalinowski). 9. Principal component analysis as a tool in organic chemistry and food chemistry (R.I. Zalewski). 10. Quantitative structure-activity relationships (D.J. Livingstone). 11. The quantitative description of steric effects (M. Charton). Index.

Polymerisation of olefinic-containing monomers employing anionic initiators

Abstract: Process for anionically polymerising a conjugated 1,3-diene monomer consists of contacting the monomer in an inert hydrocarbon solvent with a monofunctional silyl ether initiator of general formula R1R2R3Si-O-A-Li where R1 to R3 are independently selected from monovalent organic substituent groups and A is a short chain hydrocarbon bridging group, to yield a polydiene having a molecular weight of typically 1,000 - 10,000, a high 1.4 content of typically 90 % and a low polydispensity of typically 1.15. The reactive ends of the living polymer chains may be terminated with a reactive group such as hydroxyl by treating the polymer with ethylene oxide. Subsequent removal of the polymer's relatively unreactive silyl end groups by reaction with tetra-n-butylammonium fluoride produces a difunctional, chain-extendable, hydroxy-terminated polydiene useful as a rubbery binder prepolymer.

Synthesis and structure-activity relationships of benzo[b]thienylallylamine antimycotics.

Abstract: Benzo[b]thiophene analogues of the allylamine antimycotic terbinafine (2) bearing the side chain at various positions and optionally substituted by halogen have been prepared and their antifungal activity studied. Derivatives bearing the side chain at positions 3, 4, or 7 are bioequivalents of 2. Compounds containing the allylamine side chain at position 7, with a further substituent at position 3, showed significantly enhanced activity against Candida albicans, an effect which appears to be specifically linked only to this particular substitution pattern. 3-Chloro-7-benzo[b]thienyl derivative 7m was found to be the most potent allylamine antimycotic identified so far. In general, substituted benzo[b]thiophenes can be used not only as potential equivalents of naphthalene in bioactive compounds but also as a tool to selectively modify biological activities.

Cholinergic activity of acetylenic imidazoles and related compounds.

Abstract: A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cholinergic agents with in vitro binding assays and in vivo pharmacological tests in mice. 1-[4-(1H-Imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (1b) was a cholinergic agonist with one-half the potency of oxotremorine. Analogues of 1b with a 5- or 2-methyl substituent in the imidazole ring (compounds 1c and 1g) were cholinergic partial agonists. Analogues of 1b with a methyl substituent at the 5-position in the pyrrolidinone ring (7b) or at the alpha-position in the acetylenic chain (8b) were antagonists. Various analogues of these imidazole acetylenes where the pyrrolidinone ring was replaced by an amide, carbamate, or urea residue were prepared. Several compounds which contained 5-methylimidazole as the amine substituent were partial agonists. The activities of the imidazole compounds are compared with those of the related pyrrolidine and dimethylamine analogues. Agonist and antagonist conformations for these compounds at muscarinic receptors are proposed.