Steric and Stereochemical Modulation in Pyridyl- and Quinolyl-Containing Ligands
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molecules Review Steric and Stereochemical Modulation in Pyridyl- and Quinolyl-Containing Ligands Zhaohua Dai Department of Chemistry and Physical Sciences, Forensic Science Program, Pace University, 1 Pace Plaza, New York, NY 10038, USA; [email protected]; Tel.: +1-212-346-1760 Academic Editor: Derek J. McPhee Received: 24 October 2016; Accepted: 28 November 2016; Published: 1 December 2016 Abstract: Nitrogen-containing pyridine and quinoline are outstanding platforms on which excellent ionophores and sensors for metal ions can be built. Steric and stereochemical effects can be used to modulate the affinity and selectivity of such ligands toward different metal ions on the coordination chemistry front. On the signal transduction front, such effects can also be used to modulate optical responses of these ligands in metal sensing systems. In this review, steric modulation of achiral ligands and stereochemical modulation in chiral ligands, especially ionophores and sensors for zinc, copper, silver, and mercury, are examined using published structural and spectral data. Although it might be more challenging to construct chiral ligands than achiral ones, isotropic and anisotropic absorption signals from a single chiroptical fluorescent sensor provide not only detection but also differentiation of multiple analytes with high selectivity. Keywords: pyridine; quinoline; ionophore; sensor; steric effect; stereochemical control; metal ions; chiroptical; selectivity; differentiation 1. Introduction As nitrogen-containing aromatic compounds, pyridine and quinoline can form complexes with many metal ions because the lone pair electrons on the nitrogen are available for coordination since they are not part of the aromatic systems. The aromatic ring of pyridine or quinoline itself is a rigid platform, which can be incorporated into many achiral and chiral binding pockets to build ligands of different affinities to different metal ions. Chiral pyridyl- or quinolyl-containing ligands and their metal complexes are used as catalysts in asymmetric catalysis [1]. A recent review described the design principle for selective metal ion binding and sensing using many achiral pyridyl-containing ligands [2]. There are some other examples of achiral pyridyl-containing ligands used for metal sensing and this article will discuss the structural features of some of them [3–6]. This article mainly focuses on the stereochemical approach to achieving selective metal binding and sensing using pyridyl-/quinolyl containing ligands, especially chiral ligands. The structure-activity relationship in the modulation of coordination chemistry and/or signal transduction using such ligands/sensors will be discussed. 2. Steric and Stereochemical Modulation of Binding Affinity and Selectivity According to Comba [7], the design of a selective ligand for a metal ion must involve a high degree of preorganization for the specific metal ion and also a high degree of “disorganization” or mismatch for competing metal ions. The latter is not an easy task and it has not been addressed in detail. Still et al. pointed out that an important principle in the rational design of synthetic host molecules is using substitution and stereochemistry to reduce the populations of conformations unfavorable to binding [8]. By the same token, substitution and stereochemistry manipulation should be able to reduce the population of conformations favorable to binding, thus enabling the manipulation of selectivity. Molecules 2016, 21, 1647; doi:10.3390/molecules21121647 www.mdpi.com/journal/molecules Molecules 2016, 21, x 2 of 19 Moleculesbe able2016 to , 21reduce, 1647 the population of conformations favorable to binding, thus enabling2 ofthe 20 manipulation of selectivity. 2+ 2+ 2.1. Steric Control of AchiralAchiral Ligands’ Selectivity to Zn2+ andand Cu Cu2+ Many ionophoresionophores are are incorporated incorporated in sensors in sensor for metals for ions metal and otherions and species. other Signal species. transduction Signal oftransduction many sensing of many events sensing depends events on the depends structure on and the conformation structure and of theconformation analyte-sensor of the complexes. analyte- 2+ Insensor the developmentcomplexes. In ofthe Zn developmentchelators of and Zn sensors,2+ chelators specificity and sensors, to zinc specificity is highly to desirable zinc is highly from 2+ manydesirable perspectives. from many Overperspectives. the years, Over some the sensitive years, some fluorescent sensitive sensors fluorescent for Zn sensors, which for Zn are2+, mostly which N-containingare mostly N-containing ligands, have ligands, been have developed been developed and their selectivityand their selectivity against some against other some metal other ions metal has 2+ beenions has investigated been investigated [6,9–21]. However,[6,9–21]. However, as predicted as bypredicted the Irving-Williams by the Irving-Williams series [22], Cuseriescomplexes [22], Cu2+ 2+ withcomplexes nitrogen with donor nitrogen ligands dono arer ligands typically are found typically to befound more to stable be more than stable Zn thancomplexes Zn2+ complexes by several by 10 2+ ordersseveral of orders magnitude: of magnitude: Complexation Complexation with d withmetal d10 ion metal Zn ionoffers Zn2+ no offers ligand no fieldligand stabilization field stabilization energy (LFSE)energy [(LFSE)23]. For [23]. example, For example, macrocycles macrocycles are ideal are for ideal the for selective the selective coordination coordinati of alkalion of alkali or alkali or alkali earth metals,earth metals, which which can be can discriminated be discriminated from each from other each solelyother onsolely the basison the of basis their of ionic their radii ionic and radii charge. and 2+ 2+ However,charge. However, they may they be lessmay useful be less in useful distinguishing in distinguishing Cu from Cu Zn2+ frombecause Zn2+ because the radii the of theseradii ionsof these are 2+ almostions are identical. almost identical. This is reflected This isin reflected the relative in the binding relative affinities binding of macrocyclicaffinities of ligandsmacrocyclic toward ligands Zn 2+ andtoward Cu Zn, where2+ and Cu the2+ latter, where is favoredthe latter by is 10–15 favored orders by 10 of–15 magnitude orders of [ 21magnitude,24]. [21,24]. 2+ One simple Schiff base sensor exhibitsexhibits ZnZn2+-chelation-chelation enhanced enhanced fluorescence, fluorescence, which which suffers from 2+ interference fromfrom CuCu2+.. A A subtle subtle structural structural change change can can turn turn such such a a ligand ligand platform platform from from an an enol-imine enol-imine 2+ 2+ tautomer to a keto-enamine tautomer,tautomer, whichwhich isis muchmuch moremore selectivelyselectively forfor ZnZn2+ over Cu 2+ [25].[25]. I/II Rorabacher et alal.. examined the steric effecteffect onon CuCuI/II redoxredox couples [26]. [26]. They They found found that in aqueous solution for 35 different tripodaltripodal ligands,ligands, manymany ofof whichwhich areare tris(2-pyridylmethyl)aminetris(2-pyridylmethyl)amine + (TPA, FigureFigure1 1)) analogs analogs with with different different substituents, substituents, the the stability stability constants constants of of their their Cu Cu+ complexes are 12 16 in the relatively narrownarrow rangerange ofof 101012–1016 althoughalthough they they are are hugely hugely different different in terms of coordination 2+ geometry andand donor donor strength, strength, while while those those of their of Cutheircomplexes Cu2+ complexes stretch overstretch 26 ordersover of26 magnitude.orders of 2+ Itmagnitude. was suggested It was thatsuggested ligand that coordination ligand coordination geometry geometry mainly impactsmainly impacts the complexation the complexation of Cu of, + whileCu2+, while imposing imposing little effectlittle effect on Cu on. Cu+. N N N N N N N N N N N N (a) (b) Figure 1. StructuresStructures of of ( (aa)) compound compound 11,, tris(2-pyridylmethyl)amine tris(2-pyridylmethyl)amine (TPA) (TPA) and and ( (b)) compound 2,, parabenzobis-TPA (PBTPA).(PBTPA). Because of its 3d104s0 configuration, Zn2+, like Cu+ [22], is not strongly influenced by constraints Because of its 3d104s0 configuration, Zn2+, like Cu+ [22], is not strongly influenced by constraints in its coordination configuration. Therefore, it is necessary to make a ligand which has a high degree in its coordination configuration. Therefore, it is necessary to make a ligand which has a high degree of of predisorganization for Cu2+ so that it can show better Zn2+/Cu2+ selectivity. As a d9 metal, the predisorganization for Cu2+ so that it can show better Zn2+/Cu2+ selectivity. As a d9 metal, the bonding bonding in Cu2+ complexes is partially covalent. At the same time, Cu2+ prefers 4-coordinate square in Cu2+ complexes is partially covalent. At the same time, Cu2+ prefers 4-coordinate square planar planar and 5-coordinate square pyramidal geometries over tetrahedral and trigonal bipyramidal and 5-coordinate square pyramidal geometries over tetrahedral and trigonal bipyramidal geometries geometries according to Crystal Field Theory [27]. C3 or pseudo-C3 symmetrical N-containing TPA according to Crystal Field Theory [27]. C or pseudo-C symmetrical N-containing TPA derivatives derivatives bind Cu2+ much better than Zn3 2+ as predicted3 by the Irving-Williams series [22]. At the bind Cu2+ much better than Zn2+ as predicted by the Irving-Williams series [22]. At the same time, same time, they are naturally trigonal bipyramidal