Mark S. Taylor

Anion Receptors Composed of Hydrogen- and Halogen-Bond Donor Groups: Modulating Selectivity With Combinations of Distinct Noncovalent Interactions

Studies of a series of urea-based anion receptors designed to probe the potential for anion recognition through combinations of hydrogen and halogen bonding are presented. Proton- and fluorine-NMR spectroscopy indicates that the two interactions act in concert to achieve binding of certain anions, a conclusion supported by computational studies. Replacement of the halogen-bond donating iodine substituent by fluorine (which does not participate in halogen bonding) enables estimation of the contribution of this interaction to the free energy of anion binding. Evidence for attractive contacts between anions and electron-deficient arenes arising from the use of perfluoroarene-functionalized ureas as control receptors is also discussed. The magnitude of the free energy contribution of halogen bonding depends both on the geometric features of the group linking the hydrogen- and halogen-bond donor groups and on the identity of the bound anion. The results are interpreted in relation to fundamental features of the halogen-bonding interaction, including its directionality and unusual preference for halides over oxoanions. Cooperation between two distinct noncovalent interactions leads to unusual effects on receptor selectivity, a result of fundamental differences in the interactions of halogen- and hydrogen-bond donor groups with anions.

Thermodynamics of halogen bonding in solution: substituent, structural, and solvent effects.

A detailed study of the thermodynamics of the halogen-bonding interaction in organic solution is presented. (19)F NMR titrations are used to determine association constants for the interactions of a variety of Lewis bases with fluorinated iodoalkanes and iodoarenes. Linear free energy relationships for the halogen bond donor ability of substituted iodoperfluoroarenes XC(6)F(4)I are described, demonstrating that both substituent constants (sigma) and calculated molecular electrostatic potential surfaces are useful for constructing such relationships. An electrostatic model is, however, limited in its ability to provide correlation with a more comprehensive data set in which both halogen bond donor and acceptor abilities are varied: the ability of computationally derived binding energies to accurately model such data is elucidated. Solvent effects also reveal limitations of a purely electrostatic depiction of halogen bonding and point to important differences between halogen bonding and hydrogen bonding.

A study of prognostic factors for hepatic resection for colorectal metastases

BACKGROUND Liver resection is accepted treatment for selected patients with colon cancer metastatic to the liver. There remains some controversy regarding the selection criteria, particularly which preoperative features are useful predictors of long survival postresection. METHODS One hundred and twenty-three patients who had liver resection for colorectal metastases on the Hepato Pancreatic Biliary Service at The Toronto Hospital between August 1977 and June 1993 were studied. Seventy-seven had solitary lesions, 15 had single lesions with satellite nodules, and 31 had multiple lesions. Synchronous liver metastases were found in 40 patients and 83 patients had metachronous lesions. Fifty-one patients had formal lobectomies and 21 had extended lobectomies. RESULTS Postoperative complications were seen in 28% of patients, but there were no operative or postoperative deaths. Overall actuarial 5-year survival was 34%. There was a significant difference in survival according to the number of metastases. Patients with single lesions had a 5-year survival of 47% compared with 16% for single lesions with satellite nodules, and 17% for multiple lesions. There were no significant differences in survival based on age, sex, synchronous versus metachronous lesions, status of lymph nodes at the time of original surgery, intraoperative blood replacement, or size of tumor. CONCLUSIONS An aggressive approach to the surgical management of colorectal liver metastases is possible with low risk in centers specializing in liver surgery, and results in prolonged survival in one third of patients. The most reliable predictor of long-term survival is the number of metastases in the liver.

A Tridentate Halogen-Bonding Receptor for Tight Binding of Halide Anions†

The selective recognition of anions by synthetic receptors is a problem that continues to fascinate chemists. Hydrogen bonding has been the most frequently employed noncovalent interaction for the design of such receptors: molecular scaffolds that place H-bond donor groups in geometries suitable for an anion of interest demonstrate remarkable levels of selectivity and affinity. Nonetheless, anion receptors that rely upon other noncovalent forces, including Lewis acid–base and anion–p interactions, have been investigated, with considerable success. Such studies have provided insight into the interactions employed, and have offered new opportunities to achieve selectivity in anion recognition. Here, we describe simple receptors capable of tight binding of halide anions through multidentate halogen bonding interactions (Figure 1). These represent the first systems in which the cooperative action of multiple halogen-bond donors is employed to achieve high-affinity binding in dilute solution. The selectivities of these receptors differ substantially from those of related receptors based on hydrogen bonding. Although halogen bonds between electron-deficient organohalides and electron donors were observed decades ago, it is only recently that the generality and utility of this noncovalent interaction have gained widespread appreciation. Halogen bonding has now been established as a powerful strategy for self-assembly in condensed phases, and its implications in biological systems are emerging. Anions, particularly halides, participate readily as halogen-bond acceptors in the solid state, including examples of crystalline networks in which a single anion accepts multiple halogen bonds. This last observation suggests that a multidentate halogen-bond donor capable of donating several halogen bonds in a convergent fashion might be capable of anion binding in dilute solution. Designing such a receptor presented a challenge. Applications of halogen bonding in self-assembly have relied extensively on para-substituted iodotetrafluorobenzene derivatives prepared by nucleophilic aromatic substitution (for example, 2a). This strategy results in divergent arrays of halogen-bond donors useful for constructing noncovalent polymers as well as twoand three-dimensional networks. In contrast, it is poorly suited for orienting multiple donors in a convergent fashion for binding to a single acceptor as is generally required of a high-affinity host. 2] The most successful example of anion binding by a halogen-bond donor achieved to date makes use of ion-pair recognition: receptor 2 a shows a 20-fold higher affinity for sodium iodide than does control receptor 2 b, indicating a modest but measurable increase in affinity resulting from halogen bonding of iodide to the iodoarene groups (Figure 1). We chose to explore ortho-substituted iodoperfluoroarenes as the basis for receptors capable of multidentate halogen bonding. Esters of 2,3,4,5-tetrafluoro-6-iodobenzoic acid (which is easily prepared on multigram scale in one step) emerged as attractive targets (1a–1d, Figure 1): we anticipated that the electron-withdrawing carboxy group would promote halogen-bond donor ability, while enabling a straightforward receptor synthesis through coupling reactions of readily available diols and triols. Receptors 1b and 1c were prepared to test the feasibility of bidentate halogen Figure 1. Structures of the multivalent halogen-bond donors 1a–1d, and the ion-pair receptor 2a of Resnati and co-workers (Ref. [11a]).

Borinic Acid-Catalyzed Regioselective Acylation of Carbohydrate Derivatives

Reversible covalent interactions of organoboron compounds are exploited as the basis for regioselective borinic acid-catalyzed acylations of polyols. This catalytic protocol enables differentiation of the secondary OH groups of a wide range of carbohydrate derivatives with diverse acid chloride and chloroformate reagents, using a structurally simple diarylborinic acid-derived catalyst.

Regioselective Activation of Glycosyl Acceptors by a Diarylborinic Acid-Derived Catalyst

A derivative of diphenylborinic acid promotes catalytic, regioselective Koenigs-Knorr glycosylations of carbohydrate derivatives bearing multiple secondary hydroxyl groups. Robust levels of selectivity for the equatorial OH group of cis-1,2-diol motifs are demonstrated in reactions of seven acceptors derived from galactose, mannose, fucose, and arabinose using a variety of glycosyl halide donors. Catalyst control presents a new means of generating defined glycosidic linkages from unprotected or minimally protected carbohydrate feedstocks.

Regioselective, Borinic Acid-Catalyzed Monoacylation, Sulfonylation and Alkylation of Diols and Carbohydrates: Expansion of Substrate Scope and Mechanistic Studies

Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the-art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.

Chalcogen Bonding in Solution: Interactions of Benzotelluradiazoles with Anionic and Uncharged Lewis Bases

Chalcogen bonding is the noncovalent interaction between an electron-deficient, covalently bonded chalcogen (Te, Se, S) and a Lewis base. Although substantial evidence supports the existence of chalcogen bonding in the solid state, quantitative data regarding the strengths of the interactions in the solution phase are lacking. Herein, determinations of the association constants of benzotelluradiazoles with a variety of Lewis bases (Cl(-), Br(-), I(-), NO3(-) and quinuclidine, in organic solvent) are described. The participation of the benzotelluradiazoles in chalcogen bonding interactions was probed by UV-vis, (1)H and (19)F NMR spectroscopy as well as nano-ESI mass spectrometry. Trends in the free energy of chalcogen bonds upon variation of the donor, acceptor and solvent are evident from these data, including a linear free energy relationship between chalcogen bond donor ability and calculated electrostatic potential at the tellurium center. Calculations using the dispersion-corrected B97-D3 functional were found to give good agreement with the experimental free energies of chalcogen bonding.

Correlations between Computation and Experimental Thermodynamics of Halogen Bonding

Correlations between experimental, solution-phase thermodynamic data and calculated gas-phase energies of interaction are investigated for noncovalent halogen bonding interactions between electron-deficient iodo compounds and Lewis bases. The experimental data consist of free energies of interaction spanning roughly 7 kcal/mol; they encompass halogen bonds involving both organic (iodoperfluoroarene or iodoperfluoroalkane) and inorganic (I(2), IBr, ICN) donors with nitrogen- and oxygen-based acceptors and are divided into two sets according to the identity of the solvent in which they were determined (alkanes or CCl(4)). Adiabatic energies of halogen bonding were calculated using a variety of methods, including 22 DFT exchange-correlation functionals, using geometries optimized at the MP2/6-31+G(d,p) level of theory. Certain DFT functionals, particularly the B97-1, B97-2, and B98 family, provide outstanding linear correlations with the experimental thermodynamic data, as assessed by a variety of statistical methods.

Regioselective Alkylation of Carbohydrate Derivatives Catalyzed by a Diarylborinic Acid Derivative

Regioselective, catalyst-controlled monoalkylations of cis-vicinal diol motifs in carbohydrate derivatives, using a diphenylborinic ester precatalyst, are described. Selective installation of benzyl, naphthylmethyl, 4-bromobenzyl and benzyloxymethyl protective groups at a single secondary hydroxy group of ten representative carbohydrate derivatives illustrates the scope of this method. This new mode of catalytic reactivity represents an operationally simple method to access useful monoalkylated building blocks while avoiding the use of stoichiometric quantities of organotin reagents.