Allenamides as a Powerful Tool to Incorporate Diversity: Thia-Michael Lipidation of Semisynthetic Peptides and Access to ß-Keto Amides.

Lipopeptides are an important class of biomolecules for drug development. Compared with conventional acylation, a chemoselective lipidation strategy offers a more efficient strategy for late-stage structural derivatisation of a peptide scaffold. It provides access to chemically diverse compounds possessing intriguing and non-native moieties. Utilising an allenamide, we report the first semisynthesis of antimicrobial lipopeptides leveraging a highly efficient thia-Michael addition of chemically diverse lipophilic thiols. Using chemoenzymatically prepared polymyxin B nonapeptide (PMBN) as a model scaffold, an optimised allenamide-mediated thia-Michael addition effected rapid and near quantitative lipidation, affording vinyl sulfide-linked lipopeptide derivatives. Harnessing the utility of this new methodology, 22 lipophilic thiols of unprecedented chemical diversity were introduced to the PMBN framework. These included alkyl thiols, substituted aromatic thiols, heterocyclic thiols and those bearing additional functional groups (e.g., amines), ultimately yielding analogues with potent Gram-negative antimicrobial activity and substantially attenuated nephrotoxicity. Furthermore, we report facile routes to transform the allenamide into a ß-keto amide on unprotected peptides, offering a powerful "jack-of-all-trades" synthetic intermediate to enable further peptide modification.

Computational investigation of cycloadditions between cyclopentadiene and tropone-3,4-dimethylester.

Thermally promoted cycloaddition reactions of tropone-3,4-dimethylester and cyclopentadiene have been investigated using density functional theory calculations at the M06-2X level and the CBS-QB3 method. The reaction shares several characteristics with previously investigated cycloadditions involving unsubstituted tropone and cyclopentadiene, however substitution of the tropone component with methyl esters results in lower transition state free energy barriers, greater thermodynamic driving forces, and a significant increase in the number of possible pericyclic reaction pathways. Eighteen different [4 + 2], [6 + 4], or [8 + 2] cycloaddition products are possible and many of the initially formed cycloadducts can be interconverted through Cope or Claisen rearrangements. Of the many possible cycloaddition products only two are predicted to form: the exo-[6 + 4] product and one [4 + 2] product where the substituted tropone appears to be the diene. The two computationally predicted products are the same as the two that are observed experimentally, however computations indicate that both products result from ambimodal processes rather than single-step (monomodal) cycloaddition pathways.

Electronic Spectroscopy of 2-Phenyl-1,3,2-benzodioxaborole and Its Derivatives: Important Building Blocks of Covalent Organic Frameworks.

Aryl boronate esters, such as 2-phenyl-1,3,2-benzodioxaborole (1), are important components in the formation of a variety of covalent organic frameworks. The addition of substituents on the aromatic rings of aryl boronate esters has the potential to modify the structure, reactivity, and electronic properties of the resulting materials, and so, it is useful to understand at a more fundamental level the properties of these important compounds. Experimental measurements and computational investigations are presented herein that provide insight regarding the structural and electronic properties of parent aryl boronate ester 1 as well as three substituted derivatives: 2-(o-tolyl)-1,3,2-benzodioxaborole (2), 2-(2,6-dimethylphenyl)-1,3,2-benzodioxaborole (3), and 2-(4-(tert-butyl)phenyl)-1,3,2-benzodioxaborole (4). Electronic spectroscopy combined with excited-state calculations reveal two closely spaced electronic states, S1 and S2, which appear to have excitation primarily localized on the aromatic system of the phenyl substituent or the catecholborane moiety, respectively. Interestingly, the ortho-dimethyl derivative (3) shows a significantly red-shifted electronic origin with an extensive vibronic progression of a low-frequency torsional motion about the C-B bond. Franck-Condon calculations on the ab initio determined ground- and excited-state potentials very accurately reproduce this spectrum, confirming the nonplanar ground state of this compound.

Dendritic architectures by orthogonal thiol-maleimide "click" and furan-maleimide dynamic covalent chemistries.

A set of dendrons and dendrimers is synthesized divergently using an orthogonal combination of kinetically-driven thiol-maleimide "click" chemistry and thermodynamically reversible furan-maleimide cycloaddition/retrocycloaddition reactions. Growth is controlled by taking advantage of the selective thiol-ene addition of thiols to the electron withdrawn alkene of maleimide in the presence of electron rich alkene of oxanorbornene. Subsequent activation of growing dendrons/dendrimers requires only heat to induce the dynamic covalent liberation of peripheral furan protecting groups. The methodology introduced provides a new route to multifunctional dendrimers that could, in principle, be synthesized by introducing different branched monomers at any stage of dendrimer growth, allowing dendrimer architectures and properties to be better tailored to their intended applications.

Evaluating Nucleophile Byproduct Formation during Phosphine- and Amine-Promoted Thiol-Methyl Acrylate Reactions.

The commonly accepted mechanism of nucleophile-initiated thiol-acrylate reactions requires the formation of undesired nucleophile byproducts. A systematic evaluation of the formation of such nucleophile byproducts has been carried out to understand the relationships between byproduct formation and nucleophile structure, stoichiometry, solvent, and reaction type. Three common nucleophiles for thiol-Michael reactions were investigated: dimethylphenylphosphine (DMPP), diethylamine (DEA), and hexylamine (HA). The formation of phosphonium ester and aza-Michael byproducts upon initiating a representative thiol-acrylate reaction between 1-hexanethiol and methyl acrylate at a range of initiator loading (0.01-10.0 equiv) and in different solvents (neat, DMSO, THF, and CHCl3) was determined by 1H NMR spectroscopy. The influence of reaction type was investigated by expanding from small molecule reactions to end group thiol-acrylate functionalization of PEG-diacrylate polymers and through investigations of polymer-polymer coupling reactions. Results indicate that the propensity of forming nucleophile byproducts varies with nucleophile type, solvent, and reaction type. Interestingly, for all but polymer-polymer ligation reactions, nucleophile byproduct formation is largely unobserved for nitrogen-centered nucleophiles DEA and HA and essentially nonexistent for the phorphorous-centered nucleophile DMPP. A rationale for the differences in nucleophile byproduct formation for DMPP, DEA, and HA is proposed and supported by experimental and computational analysis.

Investigation and Demonstration of Catalyst/Initiator-Driven Selectivity in Thiol-Michael Reactions.

Thiol-Michael "click" reactions are essential synthetic tools in the preparation of various materials including polymers, dendrimers, and other macromolecules. Despite increasing efforts to apply thiol-Michael chemistry in a controlled fashion, the selectivity of base- or nucleophile-promoted thiol-Michael reactions in complex mixtures of multiple thiols and/or acceptors remains largely unknown. Herein, we report a thorough fundamental study of the selectivity of thiol-Michael reactions through a series of 270 ternary reactions using 1H NMR spectroscopy to quantify product selectivity. The varying influences of different catalysts/initiators are explored using ternary reactions between two Michael acceptors and a single thiol or between a single Michael acceptor and two thiols using three different catalysts/initiators (triethylamine, DBU, and dimethylphenylphosphine) in chloroform. The results from the ternary reactions provide a platform from which sequential quaternary, one-pot quaternary, and sequential senary thiol-Michael reactions were designed and their selectivities quantified. These results provide insights into the design of selective thiol-Michael reactions that can be used for the synthesis and functionalization of multicomponent polymers and further informs how catalyst/initiator choice influences the reactivity between a given thiol and Michael acceptor.

Spectroscopic and Computational Investigations of The Thermodynamics of Boronate Ester and Diazaborole Self-Assembly.

The solution phase self-assembly of boronate esters, diazaboroles, oxathiaboroles, and dithiaboroles from the condensation of arylboronic acids with aromatic diol, diamine, hydroxythiol, and dithiol compounds in chloroform has been investigated by (1)H NMR spectroscopy and computational methods. Six arylboronic acids were included in the investigations with each boronic acid varying in the substituent at its 4-position. Both computational and experimental results show that the para-substituent of the arylboronic acid does not significantly influence the favorability of forming a condensation product with a given organic donor. The type of donor, however, greatly influences the favorability of self-assembly. (1)H NMR spectroscopy indicates that condensation reactions between arylboronic acids and catechol to give boronate esters are the most favored thermodynamically, followed by diazaborole formation. Computational investigations support this conclusion. Neither oxathiaboroles nor dithiaboroles form spontaneously at equilibrium in chloroform at room temperature. Computational results suggest that the effect of borylation on the frontier orbitals of each donor helps to explain differences in the favorability of their condensation reactions with arylboronic acids. The results can inform the use of boronic acids as they are increasingly utilized in the dynamic self-assembly of organic materials and as components in dynamic combinatorial libraries.

Allyl-functionalized dioxynaphthalene[38]crown-10 macrocycles: synthesis, self-assembly, and thiol-ene functionalization.

Five dioxynaphthalene[38]-crown-10 (DNP38C10) macrocycles bearing one, two, three, or four allyl moieties have been synthesized and their ability to spontaneously self-assemble with methyl viologen to form [2]pseudorotaxanes has been evaluated. Association constants between methyl viologen and several of the allyl-functionalized DNP38C10 macrocycles are found to be comparable to that of methyl viologen and unfunctionalized DNP38C10, however, the enthalpic and entropic factors that underlie overall binding free energy vary systematically with increasing allyl substitution. These variations are explained through a combination of solution phase and solid-state analysis of the macrocycles and their complexes. The utility of endowing DNP38C10 macrocycles with allyl moieties is further demonstrated by the ease with which they can be functionalized through thiol-ene click chemistry.

Experimental and theoretical studies of selective thiol-ene and thiol-yne click reactions involving N-substituted maleimides.

A combination of experimental and computational methods has been used to understand the reactivity and selectivity of orthogonal thiol-ene and thiol-yne ″click″ reactions involving N-allyl maleimide (1) and N-propargyl maleimide (2). Representative thiols methyl-3-mercaptopropionate and ß-mercaptoethanol are shown to add exclusively and quantitatively to the electron poor maleimide alkene of 1 and 2 under base (Et3N) initiated thiol-Michael conditions. Subsequent radical-mediated thiol-ene or thiol-yne reactions can be carried out to further functionalize the remaining allyl or propargyl moieties in near quantitative yields (>95%). Selectivity, however, can only be achieved when base-initiated thiol-Michael reactions are carried out first, as radical-mediated reactions between equimolar amounts of thiol and N-substituted maleimides give complex mixtures of products. CBS-QB3 calculations have been used to investigate the energetics and kinetics of reactions between a representative thiol (methyl mercaptan) with N-allyl and N-propargyl maleimide under both base-initiated and radical-mediated conditions. Calculations help elucidate the factors that underlie the selective base-initiated and nonselective radical-mediated thiol-ene/yne reactions. The results provide additional insights into how to design selective radical-mediated thiol-ene/yne reactions.

Thiol-ene click chemistry: computational and kinetic analysis of the influence of alkene functionality.

The influence of alkene functionality on the energetics and kinetics of radical initiated thiol-ene click chemistry has been studied computationally at the CBS-QB3 level. Relative energetics (ΔH°, ΔH(++), ΔG°, ΔG(++)) have been determined for all stationary points along the step-growth mechanism of thiol-ene reactions between methyl mercaptan and a series of 12 alkenes: propene, methyl vinyl ether, methyl allyl ether, norbornene, acrylonitrile, methyl acrylate, butadiene, methyl(vinyl)silanediamine, methyl crotonate, dimethyl fumarate, styrene, and maleimide. Electronic structure calculations reveal the underlying factors that control activation barriers for propagation and chain-transfer processes of the step-growth mechanism. Results are further extended to predict rate constants for forward and reverse propagation and chain-transfer steps (k(P), k(-P), k(CT), k(-CT)) and used to model overall reaction kinetics. A relationship between alkene structure and reactivity in thiol-ene reactions is derived from the results of kinetic modeling and can be directly related to the relative energetics of stationary points obtained from electronic structure calculations. The results predict the order of reactivity of alkenes and have broad implications for the use and applications of thiol-ene click chemistry.

Substituent effects on the reversibility of furan-maleimide cycloadditions.

The effects of furan and maleimide substitution on the dynamic reversibility of their Diels-Alder reactivity have been investigated computationally and by (1)H NMR spectroscopy. Furan and furan derivatives bearing methoxy, methyl, or formyl groups at their 2- or 3-positions were investigated with maleimide and maleimide derivatives bearing N-methyl, N-allyl, and N-phenyl substituents. Computational predictions indicate that electronic and regiochemical effects of furan substitution significantly influence their Diels-Alder reactivity with maleimide, with reaction free energies of exo adduct formation ranging from ΔG = -9.4 to 0.9 kcal/mol and transition state barriers to exo adduct formation ranging from ΔG(‡) = 18.9 to 25.6 kcal/mol. Much less variation was observed for the reactivity of N-substituted maleimide derivatives and furan, with reaction and transition state free energies each falling within a range of 1.1 kcal/mol. Dynamic exchange experiments monitored by (1)H NMR spectroscopy support computational predictions. The results indicate the reactivity and reversibility of furan-maleimide cycloadditions can be tuned significantly through the addition of appropriate substituents and have implications in the use of furan and maleimide derivatives in the construction of thermally responsive organic materials.

Substituent effects on the intramolecular charge transfer and fluorescence of bimetallic platinum complexes.

An investigation of a series of platinum-containing organometallic complexes for the study of fluorescence phenomena in organometallic chromophores controlled by the intramolecular charge transfer (ICT) is presented in this work. We report steady-state and time-resolved spectroscopic experiments as well as quantum chemistry calculations to investigate the substituent effects on the ICT and fluorescence emission. We demonstrate that the fluorescence maximum and lifetimes greatly depend on different substituents and the presence of bimetallic platinum donor. This work paves the way for an understanding of the fluorescence phenomena controlled by molecular ICT characters of these kinds of platinum-containing organometallic complexes.

Structures of metallosupramolecular coordination assemblies can be obtained by ion mobility spectrometry-mass spectrometry.

Rigid rectangular, triangular, and prismatic supramolecular assemblies, cyclobis[(2,9-bis[trans-Pt(PEt(3))(2)(PF(6))]anthracene)(4,4'-dipyridyl)], cyclotris[(2,9-bis[trans-Pt(PEt(3))(2)(PF(6))]phenanthrene)(4,4'-dipyridyl)], and cyclotris[bis[cis-Pt(PEt(3))(2)(CF(3)SO(3))(2)]tetrakis(4-pyridyl)cyclobutadienecyclopentadienylcobalt(I)], respectively, based on dipyridyl ligands and square planar platinum coordination, have been investigated by ion mobility spectrometry-mass spectrometry (IMS-MS). Electrospray ionization-quadrupole and time-of-flight spectra have been obtained and fragmentation pathways assigned. Ion mobility studies give cross sections that compare very well with cross sections of the supramolecular rectangle and triangle species on the basis of X-ray bond distances. For the larger prism structures, agreement of experimental and calculated cross sections from molecular modeling is very good, indicating IMS-MS methods can be used to characterize complex self-assembled structures where X-ray or other spectroscopic structures are not available.

Ultrafast optical excitations in supramolecular metallacycles with charge transfer properties.

New organometallic materials such as two-dimensional metallacycles and three-dimensional metallacages are important for the development of novel optical, electronic, and energy related applications. In this article, the ultrafast dynamics of two different platinum-containing metallacycles have been investigated by femtosecond fluorescence upconversion and transient absorption. These measurements were carried out in an effort to probe the charge transfer dynamics and the rate of intersystem crossing in metallacycles of different geometries and dimensions. The processes of ultrafast intersystem crossing and charge transfer vary between the two different classes of metallacyclic systems studied. For rectangular anthracene-containing metallacycles, the electronic coupling between adjacent ligands was relatively weak, whereas for the triangular phenanthrene-containing structures, there was a clear interaction between the conjugated ligand and the metal complex center. The transient lifetimes increased with increasing conjugation in that case. The results show that differences in the dimensionality and structure of metallacycles result in different optical properties, which may be utilized in the design of nonlinear optical materials and potential new, longer-lived excited state materials for further electronic applications.

2D assembly of metallacycles on HOPG by shape-persistent macrocycle templates.

The synthesis and scanning tunneling microscopy (STM) investigations of shape-persistent arylene-ethynylene-butadiynylene macrocycles along with their codeposites with metallacycles are reported. 2D ordered arrays of macrocycles and macrocycle/metallacycle architectures (1:1) have been obtained on HOPG by self-assembly under ambient conditions. It is found that the ordered macrocycle array acts as a template for the deposition of the adlayer molecules. For each underlying macrocycle, one metallacycle has been detected. The unit-cell data of both, the macrocycles and their codeposites, show that the structural information of the macrocycle layer is perfectly transformed to the guest molecules. A rather unexpected observation is that the present compound could not be coadsorbed with C(60), indicating that only a minor change in the structure of the macrocycle has a dramatic effect on the ability of the monolayer to bind additional guest molecules.

Self-organization in coordination-driven self-assembly.

Self-assembly allows for the preparation of highly complex molecular and supramolecular systems from relatively simple starting materials. Typically, self-assembled supramolecules are constructed by combining complementary pairs of two highly symmetric molecular components, thus limiting the chances of forming unwanted side products. Combining asymmetric molecular components or multiple complementary sets of molecules in one complex mixture can produce myriad different ordered and disordered supramolecular assemblies. Alternatively, spontaneous self-organization phenomena can promote the formation of specific product(s) out of a collection of multiple possibilities. Self-organization processes are common throughout much of nature and are especially common in biological systems. Recently, researchers have studied self-organized self-assembly in purely synthetic systems. This Account describes our investigations of self-organization in the coordination-driven self-assembly of platinum(II)-based metallosupramolecules. The modularity of the coordination-driven approach to self-assembly has allowed us to systematically study a wide variety of different factors that can control the extent of supramolecular self-organization. In particular, we have evaluated the effects of the symmetry and polarity of ambidentate donor subunits, differences in geometrical parameters (e.g., the size, angularity, and dimensionality) of Pt(II)-based acceptors and organic donors, the influence of temperature and solvent, and the effects of intermolecular steric interactions and hydrophobic interactions on self-organization. Our studies have shown that the extent of self-organization in the coordination-driven self-assembly of both 2D polygons and 3D polyhedra ranges from no organization (a statistical mixture of multiple products) to amplified organization (wherein a particular product or products are favored over others) and all the way to the absolute self-organization of discrete supramolecular assemblies. In many cases, inputs such as dipolar interactions, steric interactions, and differences in the geometric parameters of subunits, used either alone or as multiple factors simultaneously, can achieve absolute self-organization of discrete supramolecules. We have also observed instances where self-organization is not absolute and varies in its deviation from statistical results. Steric interactions are particularly useful control factors for driving such amplified self-organization because they can be subtly tuned through small structural variations. Having the ability to fully understand and control the self-organization of complex mixtures into specific synthetic supramolecules can provide a better understanding of analogous processes in biological systems. Furthermore, self-organization may allow for the facile synthesis of complex multifunctional, multicomponent systems from simply mixing a collection of much simpler, judiciously designed individual molecular components.

Surface confined metallosupramolecular architectures: formation and scanning tunneling microscopy characterization.

Metallosupramolecular compounds have attracted a great deal of attention over the past two decades largely because of their unique, highly complex structural characteristics and their potential electronic, magnetic, optical, and catalytic properties. These molecules can be prepared with relative ease using coordination-driven self-assembly techniques. In particular, the use of electron-poor square-planar Pt(II) transition metals in conjunction with rigid, electron-rich pyridyl donors has enabled the spontaneous self-assembly of a rich library of 2D metallacyclic and 3D metallacage assemblies via the directional-bonding approach. With this progress in the preparation and characterization of metallosupramolecules, researchers have now turned their attention toward fully exploring and developing their materials properties. Assembling metallosupramolecular compounds on solid supports represents a vitally important step toward developing their materials properties. Surfaces provide a means of uniformly aligning and orienting these highly symmetric metallacycles and metallacages. This uniformity increases the level of coherence between molecules above that which can be achieved in the solution phase and provides a way to integrate adsorbed layers, or adlayers, into a solid-state materials setting. The dynamic nature of kinetically labile Pt(II)-N coordination bonds requires us to adjust deposition and imaging conditions to retain the assemblies' stability. Toward these aims, we have used scanning tunneling microscopy (STM) to image these adlayers and to understand the factors that govern surface self-assembly and the interactions that influence their structure and stability. This Account describes our efforts to deposit 2D rectangular and square metallacycles and 3D trigonal bipyramidal and chiral trigonal prism metallacages on highly oriented pyrolytic graphite (HOPG) and Au(111) substrates to give intact assemblies and ordered adlayers. We have investigated the effects of varying the size, symmetry, and dimensionality of supramolecular adsorbates, the choice of substrate, the use of a molecular template, and the effects of chirality. Our systematic investigations provide insights into the various adsorbate-adsorbate and substrate-adsorbate interactions that largely determine the architecture of each assembly and affect their performance in a materials setting. Rational control over adlayer formation and structure will greatly enhance the potential of these supramolecules to be used in a variety of applications such as host-guest sensing/diagnostic systems, molecular electronic devices, and heterogeneous stereoselective synthesis and catalysis.

Photophysical properties of coordination-driven self-assembled metallosupramolecular rhomboids: experimental and theoretical investigations.

In this work, the photophysical properties of coordination-driven self-assembled metallosupramolecular rhomboids with the donor ligands 1,2-bis(3-pyridyl)ethyne (3a) and 1,4-bis(3-pyridyl)-1,3-butadiyne (3b) are investigated by use of both spectroscopic experiments and quantum chemistry calculations. All the geometric conformations of the chair and boat conformers of 3a and 3b are fully optimized using density functional theory. The time-dependent density functional theory method was also used to study the excited-state properties of these self-assembled metallosupramolecular rhomboids. At the same time, steady-state absorption and fluorescence as well as the time-correlated single photon counting techniques are used to measure their various spectral properties. The fluorescence spectra of these self-assembled metallosupramolecular rhomboids are very wide and show an evident two-peak feature, which can be tuned by different excitation wavelengths. It has been demonstrated that the chair conformers of both 3a and 3b are formed preferentially over their boat conformers due to the close proximity of the chelated bisphosphine platinum groups. Moreover, an additional shoulder observed at 416 nm in the fluorescence spectra of 3b indicates the presence of minor amounts of the boat conformer of 3b. In addition, we have also demonstrated that lengthening the acetylene chain of the donor ligand component of these rhomboids results in a red-shifted and broadened absorption band for these metallosupramolecular rhomboids. Furthermore, the nature of the excited states for these metallosupramolecular rhomboids varies with the acetylene chain length of the donor ligands and with the different conformers.

The effect of intermolecular hydrogen bonding on the fluorescence of a bimetallic platinum complex.

The bimetallic platinum complexes are known as unique building blocks and arewidely utilized in the coordination-driven self-assembly of functionalized supramolecular metallacycles. Hence, photophysical study of the bimetallic platinum complexes will be very helpful for the understanding on the optical properties and further applications of coordination-driven self-assembled supramolecular metallacycles. Herein, we report steady-state and time-resolved spectroscopic experiments as well as quantum chemistry calculations to investigate the significant intermolecular hydrogen bonding effects on the intramolecular charge transfer (ICT) fluorescence of a bimetallic platinum compound 4,4'-bis(trans-Pt(PEt(3))(2)OTf)benzophenone 3 in solution. We demonstrated that the fluorescent state of compound 3 can be assigned as a metal-to-ligand charge transfer (MLCT) state. Moreover, it was observed that the formation of intermolecular hydrogen bonds can effectively lengthen the fluorescence lifetime of 3 in alcoholic solvents compared with that in hexane solvent. At the same time, the electronically excited states of 3 in solution are definitely changed by intermolecular hydrogen bonding interactions. As a consequence, we propose a new fluorescence modulation mechanism by hydrogen bonding to explain different fluorescence emissions of 3 in hydrogen-bonding solvents and nonhydrogen-bonding solvents.

Byproducts formed During Thiol-Acrylate Reactions Promoted by Nucleophilic Aprotic Amines: Persistent or Reactive?

The nucleophile-initiated mechanism of thiol-Michael reactions naturally leads to the formation of undesired nucleophile byproducts. Three aza-Michael compounds representing nucleophile byproducts of thiol-acrylate reactions initiated by 4-dimethylaminopyridine (DMAP), 1-methylimidazole (MIM), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been synthesized and their reactivity in the presence of thiolate has been investigated. Spectroscopic analysis shows that each nucleophile byproduct reacts with thiolate to produce a desired thiol-acrylate product along with liberated aprotic amines DMAP, MIM, or DBU, thus demonstrating that these byproducts are reactive rather than persistent. Density functional theoretical computations support experimental observations and predict that a ß-elimination mechanism is favored for converting each nucleophile byproduct into a desired thiol-acrylate product, though an SN 2 process can be competitive (i. e. within <2.5 kcal/mol) in less polar solvents.