Pairs Of Substituents Research Articles

Axial Chirality in Alkylidene‐Cyclic Molecules

AbstractAxial chirality is an interesting stereoisomeric phenomenon in organic chemistry and a key structural feature of several organic compounds. Atropisomers such as biaryls, anilides and diaryl ethers are one type of axially chiral compounds, whose axial chirality is resulted from rotationally blocked single bond. Allenes, spiranes and alkylidenecycloalkanes are another type of axially chiral compounds and their axial chirality come from the perpendicular geometry of two pairs of substituents. The axial chirality in atropisomers, allenes and spiranes has been widely investigated and well developed, while the similar chirality in alkylidene‐cyclic molecules gained very limited attentions. This concept focuses on summarizing recent advances of axial chirality in alkylidene‐cyclic molecules and arouses the research interests to this promising field.

A Track-Based Molecular Synthesizer that Builds a Single-Sequence Oligomer through Iterative Carbon-Carbon Bond Formation

Summary We report an artificial molecular machine that moves along a track, iteratively joining building blocks to form an oligomer of single sequence with a continuous backbone of carbon-carbon bonds. The rotaxane features a macrocycle bearing an aldehyde-terminated chain and an axle containing different phosphonium ylides separated by rigid spacers. Each ylide is large enough to block the passage of the macrocycle, trapping the ring between the stopper at the terminus of original threading and the next ylide along the track. Once a building block is reachable, it is removed from the track through a Wittig reaction that adds it to the terminus of the growing chain. Operation on a four-barrier tetra(phosphonium salt) track produces a tetra(diphenylpropane) of single sequence linked through alkene bonds. The prototype extends the principle for molecular machines that build polymers by moving along tracks to the synthesis of sequence-encoded chains with continuous carbon backbones.

1,5]-Sigmatropic Shifts Regulated by Built-in Frustration.

Conceptually, many organic reactions involve a flow of electron density from electron-rich to electron-poor regions. When the direct flow of electron density is blocked, the innate "frustration" can provide a driving force for a reaction that removes the blockade. Herein, we show how this idea can be used for the design of molecular rearrangements promoted by remotely placed donor-acceptor pair of substituents. We evaluate effects of such "frustration" on the rates of competing [1,5]-hydrogen and [1,5]-halogen shifts in boron-substituted 1,3-pentadienes. As the sp3 hybridized carbon (C1) in these dienes interrupts the conjugation path between the donor to the acceptor, the system conceptually resembles a frustrated Lewis pair (FLP). Frustration is weakened when the formation of a new chemical bond in the TS opens communication between electron-rich and -poor regions and is removed completely when the resonance interaction between donor and acceptor develops fully in the rearranged product. Such relief of chemical frustration is directly translated into more favorable thermodynamic driving force and decreased intrinsic activation energies. Marcus theory separates thermodynamic contribution to the activation barriers and suggests that the electronic communication between electron rich and poor regions lowers the activation barrier via the formation of stabilizing 3-center contacts in the TS. Dramatic TS stabilization illustrates that the migrating groups function as an electronic relay between migration origin and terminus with properties fine-tuned by the boronyl acceptor. The combined effects of the C-X bond strength (X = migrating group), Lewis acidities of the acceptors, thermodynamic driving forces, and secondary orbital interactions control the observed barrier trends and selectivity of migration.

Computer-aided design of short-lived phosphorescent Ru(II) polarity probes

Fluorescent polarity probes are usually based on intramolecular charge transfer excited states of selected dyes, the behavior of which in different solvents is traditionally rationalized by the well-known Lippert-Mataga treatment of the “general solvents effect”. Less often transition metal coordination complexes are used as luminescent probes, even though the spectroscopic properties of these dyes are usually dependent on the environment. This is the case of Ru(II) polypyridyls, which are good candidates to develop robust sensitive polarity probes because of their lowest-lying metal-to-ligand charge transfer triplet emissive state, provided their chelating ligands structure is judiciously tuned. The aim of this work has been to design a computational strategy to forecast the behavior of polarity-sensitive Ru(II) complexes without the need to prepare a large set of candidates. In particular, we have analysed a number of complexes derived from [Ru(bpy)3]2+ by introducing different pairs of substituents in the 4,4′ positions of one of the three equivalent 2,2′-bipyridine (bpy) moieties. In this way, we have investigated if a direct relationship may be established between the electronic features of the substituent and the Stokes shift sensitivity to the solvent polarity. Our computational data satisfactorily agree with our experimental results, but they demonstrate that only by explicitly performing the calculation of the Stokes shift in different media for each candidate, it is possible to select the best Ru(II) dyes to be used as polarity probes.

Inheritance of Photochromic Properties of Nitro-Substituted and Halogenated Spiropyrans Containing the Pyrrolidino[60]fullerene.

The photophysical and isomerization properties of hybrid molecular compounds that consist of photochromic nitro-substituted and halogenated spiropyran derivatives bonded to the surface of the [60]fullerene cage through the pyrrolidine bridge were investigated using various functionals and basis sets of TD-DFT and semiempirical quantum-chemical approaches. The role of nπ* states formed by the lone pairs of substituents in changing of the electronic structure and photochromic properties of spiropyran derivatives was evaluated. The Sππ(spiropyran) → intermediate nπ* states → Sππ(merocyanine) channel for phototransformation of the hybrid compound containing a nitro-substituted spiropyran moiety was established and compared with similar systems of halogenated spiropyrans attached to the [60]fullerene bulk where photoinduced isomerization does not process due to high probability of internal conversion from the excited electronic state localized on the spiropyran fragment to the states of the pyrrolidino[60]fullerene.

Formation of borata-alkene/iminium zwitterions by ynamine hydroboration.

The ynamine TMP-C[triple bond, length as m-dash]C-CH3 adds HB(C6F5)2 to give the unsaturated C2-bridged N/B FLP 5. Compound 5 shows the structural data indicating a marked participation of the zwitterionic mesomeric borata-alkene/iminium form. It splits dihydrogen at r.t. with Z- to E-isomerization at the central C[double bond, length as m-dash]C double bond. Hydroboration of the ynamine Me3Si-C[triple bond, length as m-dash]C-NiPr2 with HB(C6F5)2 yields a N/B FLP that shows a strongly distorted central C[double bond, length as m-dash]C double bond with a rotation of the planes of the substituent pairs at its ends by ca. 57°.

Controlling the local arrangements of π-stacked polycyclic aromatic hydrocarbons through substituent effects

PAHs such as coronene and hexa-peri-hexabenzocoronene (HBC, a nanographene) are commonly used in discotic liquid crystals, for which achieving long-range columnular order is vital for the development of materials with maximized charge-transfer rates. We demonstrate that simple substituents can have a dramatic impact on the local orientation of π-stacked polycyclic aromatic hydrocarbons (PAHs), even in the absence of steric or other non-covalent interactions (e.g.: hydrogen bonds). The strong dependence of these π-stacking interactions on the relative position of substituents is a result of the direct, through-space interactions of aryl substituents. B97-D/TZV(2d,2p) interaction energies are presented for stacked dimers of substituted benzenes, coronenes, and HBC, which display diverse orientation potentials depending on the nature of the substituents. The results show that the position of the global energy minimum for stacked PAHs depends on the nature of the aryl substituents. The preferred arrangement of stacked coronenes, for example, can be shifted from a fully staggered arrangement to a fully eclipsed arrangement through the introduction of complementary pairs of substituents.

Single R-Group Polymorphisms (SRPs) and R-Cliffs: An Intuitive Framework for Analyzing and Visualizing Activity Cliffs in a Single Analog Series

We introduce Single R-Group Polymorphisms (SRPs, pronounced 'sharps'), an intuitive framework for analyzing substituent effects and activity cliffs in a single congeneric series. A SRP is a pair of compounds that differ only in a single R-group position. Because the same substituent pair may occur in multiple SRPs in the series (i.e., with different combinations of substituents at the other R-group positions), SRP analysis makes it easy to identify systematic substituent effects and activity cliffs at each point of variation (R-cliffs). SRPs can be visualized as a symmetric heatmap where each cell represents a particular pair of substituents color-coded by the average difference in activity between the compounds that contain that particular SRP. SRP maps offer several advantages over existing techniques for visualizing activity cliffs: 1) the chemical structures of all the substituents are displayed simultaneously on a single map, thus directly engaging the pattern recognition abilities of the medicinal chemist; 2) it is based on R-group decomposition, a natural paradigm for generating and rationalizing SAR; 3) it uses a heatmap representation that makes it easy to identify systematic trends in the data; 4) it generalizes the concept of activity cliffs beyond similarity by allowing the analyst to sort the substituents according to any property of interest or place them manually in any desired order.

Effect of substituents on the stabilities of multiply-substituted carbon-centered radicals

The bond dissociation energies (BDEs) and radical stabilization energies (RSEs) which result from 166 reactions that lead to carbon-centered radicals of the type ˙CH(2)X, ˙CHXY and ˙CXYZ, where X, Y and Z are any of the fourteen substituents H, F, Cl, NH(2), OH, SH, CH[double bond, length as m-dash]CH(2), C[triple bond, length as m-dash]CH, BH(2), CHO, COOH, CN, CH(3), and CF(3), were calculated using spin-restricted and -unrestricted variants of the double-hybrid B2-PLYP method with the 6-311+G(3df,2p) basis set. The interactions of substituents X, Y, and Z in both the radicals (˙CXYZ) and in the precursor closed-shell molecules (CHXYZ), as well as the extent of additivity of such interactions, were investigated by calculating radical interaction energies (RIEs), molecule interaction energies (MIEs), and deviations from additivity of RSEs (DARSEs) for a set of 152 reactions that lead to di- (˙CHXY) and tri- (˙CXYZ) substituted carbon-centered radicals. The pairwise quantities describing the effects of pairs of substituents in trisubstituted systems, namely pairwise MIEs (PMIEs), pairwise RIEs (PRIEs) and deviations from pairwise additivity of RSEs (DPARSEs), were also calculated for the set of 61 reactions that lead to trisubstituted radicals (˙CXYZ). Both ROB2-PLYP and UB2-PLYP were found to perform quite well in predicting the quantities related to the stabilities of carbon-centered radicals when compared with available experimental data and with the results obtained from the high-level composite method G3X(MP2)-RAD. Particular selections of substituents or combinations of substituents from the current test set were found to lead to specially stable radicals, increasing the RSEs to a maximum of +68.2 kJ mol(-1) for monosubstituted radicals ˙CH(2)X (X = CH[double bond, length as m-dash]CH(2)), +131.7 kJ mol(-1) for disubstituted radicals ˙CHXY (X = NH(2), Y = CHO), and +177.1 kJ mol(-1) for trisubstituted radicals ˙CXYZ (X = NH2, Y = Z = CHO).

Ranking the effect of [1A(ax), 1B(eq)] versus [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H chemical shifts of γ-methylene cyclohexane ring protons using 2,2-disubstituted adamantanes as models

When two different substituents are placed in the nonbridgehead position of adamantane, the two [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane chair conformers are modeled and features of their NMR spectra can be studied from a single spectrum at 298 K. The effect of [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H resonance separation within the γ-CH 2s of cyclohexane ring is compared for various substituent pairs; this aim is approached by measuring the 1H chemical shift separation within the 4′,9′-H and 8′,10′-H methylenes from the 1H NMR spectrum of the model 2A,2B-disubstituted adamantane at 298 K.

The effect of substituent groups on the reductive degradation of azo dyes by zerovalent iron

To investigate the effects of substituent groups on the reductive degradation of azo dyes by zerovalent iron, Orange I, Orange II and Methyl Orange were selected as the model azo dyes with different substituent groups. The results showed that Orange I, Orange II and Methyl Orange could be effectively reduced by Fe 0, and the degradation of Orange I and Orange II could be described by the first-order kinetic model, while the degradation of Methyl Orange could be described by the zeroth-order kinetic model. The initial degradation rate followed the order as Orange I > Orange II > Methyl Orange under the same experimental conditions owing to the substituent effects. The degradation kinetic constants of Orange I and Orange II increased with the increase in the Fe 0 dosage, and with the decrease in the initial pH value and their initial concentration, while that of Methyl Orange increased with the decrease in the initial pH value, and with the increase in the Fe 0 dosage and their initial concentration. The results of high-performance liquid chromatography (HPLC)–mass spectra (MS) showed that sulfanilic acid was the same intermediate, while the second intermediate was 1-amino-4-naphthol for Orange I, 1-amino-2-naphthol for Orange II, and p-dimethylaminoaniline for Methyl Orange. It was suggested that the larger conjugated π system of naphthalene rings of Orange I and Orange II for the delocalization of the nonbonding electron pairs of substituents and nitrogen in the azo bond might be favorable for the degradation of Orange I and Orange II, compared with the structure of Methyl Orange. The higher degradation rate of Orange I might be ascribed to its effective electron delocalization and favorable position effects, compared with Orange II. It should be concluded that the reductive degradation of azo dyes by zerovalent iron strongly depends on the effect of substituent groups.

Calculation of Intersubstituent Similarity Using R‐Group Descriptors.

This paper discusses the calculation of the similarities between pairs of substituents on ring systems. An R-group descriptor characterizes the distribution of some atom-based property, such as elemental type or partial atomic charge, at increasing numbers of bonds distant from the point of substitution on the parent ring. The similarity between a pair of descriptors is then calculated by a comparison of the corresponding property vectors. Experiments with the BIOSTER database demonstrate the ability of such similarity measures to discriminate between bioisosteric and nonbioisosteric functional groups.

Calculation of intersubstituent similarity using R-group descriptors.

This paper discusses the calculation of the similarities between pairs of substituents on ring systems. An R-group descriptor characterizes the distribution of some atom-based property, such as elemental type or partial atomic charge, at increasing numbers of bonds distant from the point of substitution on the parent ring. The similarity between a pair of descriptors is then calculated by a comparison of the corresponding property vectors. Experiments with the BIOSTER database demonstrate the ability of such similarity measures to discriminate between bioisosteric and nonbioisosteric functional groups.

Effect of Side Groups on the Conformation of a Series of Polysiloxanes in Solution

The molecular conformation has been obtained for polysiloxane chains in which the pairs of substituents bonded at the silicon atom are CH3, CH3; C2H5, C2H5; CH3, C6H13; CH3, C16H33; and CH3, C6H5. Polysiloxanes dissolved in toluene and benzene were studied using a coupled system: Gel Permeation Chromatography/Light Scattering (GPC/LS). Attention was focused on the influence in the molecular conformation of the quality of the solvent and the type of substituent on the main chain. The results obtained were strongly dependent on the side group size and flexibility. Poly(dimethylsiloxane) samples of 273,400 and 97,600 daltons showed a semi-flexible conformation, but the sample of relatively low molecular weight (36×103 daltons) exhibited a slope of 0.6 in good solvents; i.e., demonstrated the behavior of dilute (non-overlapping) coils in a good solvent. With respect to the poly(diethylsiloxane), the source of the coil's expansion is the high mobility of the side chains. Poly(methylphenylsiloxane) exhibits a rigid rod conformation in both solvents. The orientation of the phenyl groups and the attractive interaction between these groups dominate the polysiloxane chain behavior in good solvents. For these polysiloxanes, the expansion factor value is analyzed and the influence of solvent on the polymer's unperturbed dimensions is discussed. Poly(methylhexylsiloxane) and poly(methylhexadecylsiloxane) show a spherical conformation in both solvents. This conformation may arise from strong interactions between the bulky side groups and the main chain.

Oxidative carbonylation of phenol to diphenyl carbonate catalyzed by Pd complex with 2,2′-bipyridyl ligands

Pd–2,2′-bipyridyl complexes were investigated as novel Pd catalysts for direct synthesis of diphenyl carbonate (DPC) by oxidative carbonylation of phenol using carbon monoxide (CO) and air. Pd–2,2′-bipyridyl complexes which possess a pair of substituents at 6,6′-position of 2,2′-bipyridyl moiety were found to be more effective than Pd–2,2′-bipyridyl complexes without any substituents at the 6,6′-position. The best efficiency was obtained by using PdCl 2(6,6′-Me 2bpy) (6,6′-Me 2bpy: 6,6′-dimethyl–2,2′-bipyridyl)/Mn(TMHD) 3 (TMHD: 2,2,6,6-tetramethyl–3,5-heptandionate)/(Ph 3P) 2NBr [bis(triphenylphosphoranylidene)ammonium bromide] system where TOF reached 13.17 (mol-DPC/mol-Pd h). The efficiency of our PdCl 2(6,6′-Me 2bpy)/Mn(TMHD) 3/(Ph 3P) 2NBr system was higher than that of conventional PdBr 2/Ce(Trop) 4 (Trop: tropolonate)/(Ph 3P) 2NBr system.

Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture.

Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.

Electrochemical study of the ?* probe dye 5-nitro-5?-dimethylamino-2,2?-bisthiophene

Cyclic voltamograms of the solvatochromic dye 5-nitro-5′-dimethylamino-2,2′-bisthiophene (1), introduced recently as a sensitive π* probe, were recorded in different solvents. An EPR spectrum of the anionic radical of 1 in DMSO was obtained and compared with other spectra of analogous substituted bisthiophene radicals. It was found that the presence of a donor– acceptor pair of substituents in 1−⋅ reduces significantly the rotational barrier of the radical compared with the unsubstituted bithienyl radical anion 2−⋅. This is the result of an electronic repulsion between the donor ring fragment and the added electron in the coplanar radical, which does not exist in 2−⋅. © 1998 John Wiley & Sons, Ltd.

Molecular structure and intramolecular hydrogen bonding in 4,6-dinitroresorcinol and 2,5-dinitrohydroquinone from ab initio molecular orbital calculations

Ab initio molecular orbital calculations using second-order Møller-Plesset (MP2) perturbation theory with the 6-31G ∗ basis set have been performed for 4,6-dinitroresorcinol and 2,5-dinitrohydroquinone. Both molecules are characterized by considerable hydrogen bonding between the nitro and hydroxy groups; pronounced structural changes in other parts of the molecules are observed when compared with the parent phenol and nitrobenzene molecules calculated at the same computational level. These structural changes are consistent with the notion of resonance-assisted hydrogen bonding, also observed in a series of other o-nitrophenols and similar molecules. The geometrical and energetic characteristics of the structures indicate somewhat weaker hydrogen bonding in 2,5-dinitrohydroquinone than in 4,6-dinitroresorcinol, which may be interpreted by the difference in the mutual orientation of the substituent pairs in the two compounds.

Systematic Analysis of Substituent Effects: 1. Geminal and Vicinal Interactions in Fluorochloroethanes

The contributions of individual substituents to properties of fluorochloroethanes are highly nonadditive. The nonadditivies can be accurately modeled with sums of terms describing geminal, gauche vicinal, and anti vicinal interactions between substituents. Such an approach, which requires 12 parameters per property, produces the total and zero-point energies and the lengths of the C−C bond with rms errors of 0.8 and 0.04 kcal/mol and 0.002 A, respectively. The inclusion of all three types of interactions is prerequisite to obtaining reasonably accurate estimates of molecular properties, although in the cases of the total and zero-point energies the geminal contributions strongly dominate. The present methodology is very general, making it possible to analyze and predict substituent effects in a systematic manner by summing transferable increments ascribed to individual substituents, substituent pairs, triples, etc., until the desired accuracy is attained. The substituent effects in the molecules under stu...

Synthesis of highly chiral multisubstituted binaphthyl compounds as potential new biaxial nematic and NLO materials

Abstract A number of multi substituted binaphthalene compounds were synthesized in an attempt to obtain a highly chiral biaxial nematic (Nb) phase or a good NLO material. Introduction of two pairs of substituents into the binaphthalene molecule with one of these being a nitrile group and R = C10 was successful but neither this compound nor the above esters showed any mesophases. Introduction of additional pairs of substituents proved to be difficult. Friedel-Crafts acylation to add a third pair through a ketone gave complicated mixtures of products obtained by cleavage of the ether followed by acylation. Bromination, which could lead to either the necessary nitrile substituent or esters via the acid obtained from the nitrile generally gave mixtures of bromides as expected. Some of these could be separated by chromatography and successfully converted to the nitrile. However, attempts to hydrolyze these nitrile groups usually gave mixtures of various products of incomplete hydrolysis producing compounds tha...