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This article describes recent attempts to understand the biological chemistry of lead using a synthetic biology approach. Lead binds to a variety of different biomolecules ranging from enzymes to regulatory and signaling proteins to bone matrix. We have focused on the interactions of this element in thiolate-rich sites that are found in metalloregulatory proteins such as Pbr, Znt, and CadC and in enzymes such as δ-aminolevulinic acid dehydratase (ALAD). In these proteins, Pb(II) is often found as a homoleptic and hemidirectic Pb(II)(SR)3- complex. Using first principles of biophysics, we have developed relatively short peptides that can associate into three-stranded coiled coils (3SCCs), in which a cysteine group is incorporated into the hydrophobic core to generate a (cysteine)3 binding site. We describe how lead may be sequestered into these sites, the characteristic spectral features may be observed for such systems and we provide crystallographic insight on metal binding. The Pb(II)(SR)3- that is revealed within these α-helical assemblies forms a trigonal pyramidal structure (having an endo orientation) with distinct conformations than are also found in natural proteins (having an exo conformation). This structural insight, combined with 207Pb NMR spectroscopy, suggests that while Pb(II) prefers hemidirected Pb(II)(SR)3- scaffolds regardless of the protein fold, the way this is achieved within α-helical systems is different than in β-sheet or loop regions of proteins. These interactions between metal coordination preference and protein structural preference undoubtedly are exploited in natural systems to allow for protein conformation changes that define function. Thus, using a design approach that separates the numerous factors that lead to stable natural proteins allows us to extract fundamental concepts on how metals behave in biological systems.

A series of Group 15-containing homometallic (E(2)L(3), E = P, As, Sb, Bi) and heterometallic (AsSbL(3), AsBiL(3), PSbL(3)) supramolecular cryptands were prepared by the self-assembly of pnictogen halides with dithiolate ligand or by direct transmetalation from a heavier congener. Structural characterization by single crystal X-ray diffraction shows that the E-S bond distances and S-E-S bond angles are significantly affected by the identity of the pnictogen. (1)H NMR spectroscopy reveals that the homometallic cryptands are dynamic in solution: surprisingly one ligand "flips", perturbing the C(3) symmetry of the complex and giving a new asymmetric conformer. Density functional theory calculations were carried out on both the symmetric and the asymmetric conformations of the cryptands, and the energies were compared to those observed by NMR spectroscopy. It was found that the relative stability of the asymmetric cryptand to its symmetric conformer increases with increasing size of the Group 15 element. Finally, it is reported that if two metals are present during the self-assembly process, heterometallic cryptands form. These supramolecular cryptands are reminiscent of their organic analogues, but result from a self-assembly process rather than a stepwise synthesis. Surprisingly, they possess conformational isomerism and exhibit dynamic transmetalation in their reactivity which provides access to otherwise unattainable assemblies.

An exhaustive structural survey was analyzed in combination with new structural reports on pnictogen···π interactions. The Cambridge Structural Database was searched for examples of pnictogen atoms (As, Sb, and Bi) that lie within the sum of their van der Waals radii with an arene ring. The results were analyzed, and it was concluded that the interaction distance is shorter for the heavier pnictogens due to the increasingly diffuse nature of the lone pair of electrons on the atom. A weak correlation between the distance and the angle of the interaction was found, implying that the interaction is partially covalent in nature but is primarily a dispersion interaction. These arene···π interactions can be used as driving forces for supramolecular assembly, and the crystal structures of two new arsenic-containing assemblies are presented. The combined analysis of these structures and the structural survey suggest that our supramolecular design strategy can be fine-tuned to take advantage of the pnictogen···π i...

A flurry of research activity has emerged in recent years resulting in reliable strategies for the formation of spectacular self-assembled metal-ligand clusters and capsules. Main group ions have not shared in this burst of activity. In fact, ions in this part of the periodic table have largely been overlooked for use as directing elements in self-assembly reactions, despite the need for improved chelators for main group ions for a variety of applications. This review surveys our approach to developing design strategies to prepare self-assembled nanoscale supramolecular complexes containing main group ions, with a particular emphasis on supramolecular arsenic(III) coordination chemistry.

Lead (Pb) has been recognized as a human toxin for thousands of years. In biological systems, sulfur-, oxygen- and nitrogen-containing groups coordinate lead in a variety of geometries. Upon ingestion by humans, lead is absorbed through the stomach, released into the blood and coordinated by glutathione and a variety of zinc and calcium proteins including δ-aminolevulinic acid dehydratase (ALAD), zinc finger transcription factors and calmodulin. Metal substitution and indiscriminate binding to proteins causes a loss of function, reflected in the diverse symptoms of lead poisoning. Although some lead binding proteins are induced in the presence of lead, their role in detoxification in humans is unclear. However, several types of bacteria have evolved defence mechanisms for the uptake, storage and exportation of lead. The proteins involved in regulating these defences, such as PbrR, are extremely selective for lead.

Protein design will ultimately allow for the creation of artificial enzymes with novel functions and unprecedented stability. To test our current mastery of nature's approach to catalysis, a Zn(II) metalloenzyme was prepared using de novo design. α3DH3 folds into a stable single-stranded three-helix bundle and binds Zn(II) with high affinity using His3 O coordination. The resulting metalloenzyme catalyzes the hydration of CO2 better than any small molecule model of carbonic anhydrase and with an efficiency within 1400-fold of the fastest carbonic anhydrase isoform, CAII, and 11-fold of CAIII.

The synthesis and crystal structures of two new macrocyclic compounds, As2(L2,5)2Cl2 and As2(L2,3)2Cl2, are described, where L2,3 and L2,5 are dithiolate ligands. For each compound, several diastereomeric isomers are possible (anti-“aligned”, syn-“aligned”, anti-“unaligned”, syn-“unaligned”), as shown by density functional theory (DFT) calculations, but only one is crystallized out of solution. For As2(L2,5)2Cl2, only the anti-aligned isomer crystallizes, as expected based on steric arguments and backed up by DFT calculations. Surprisingly, for As2(L2,3)2Cl2, an anti isomer crystallizes in which one As−Cl unit has folded into the macrocyclic cavity. While this goes against steric arguments and DFT calculations, this conformation best fills the space within the cavity, avoiding the entropic cost of a large void.

Treatment of 1,4-bis(2-mercaptoethyl)benzene (1) or 1,4-bis(2-bromoethyl)benzene (2) with excess SbCl3 affords new one-dimensional and two-dimensional supramolecular coordination networks. Compound 1·2SbCl3 is stabilized solely by Sb···Cl, Sb-π, and Sb···S secondary bonding interactions (SBIs), providing an unusual example of Sb(III) and a thiol interacting through an SBI rather than a strong antimony thiolate bond. 2·2SbCl3 is stabilized by Sb···Cl, Sb···Br, and Sb-π SBIs. Both compounds have higher melting points than that of SbCl3. The crystal structures of 1·2SbCl3 and 2·2SbCl3 have been determined by single crystal X-ray diffraction methods.

Three discrete supramolecular self-assembled arsenic(iii) complexes including an unusual S(4)-symmetric tetranuclear [As(4)L(2)Cl(4)] metallacyclophane and two diastereomeric cis/trans-[As(2)LCl(2)] metallacycle intermediates co-crystallize within a single crystal lattice.

Several intermediates and oligomeric mistakes in a metal-ligand self-assembly reaction are identified by 1H NMR, MALDI-MS, and XRD, providing evidence in support of multiple pathways in the "free-for-all" self-assembly process.

A flurry of research activity has emerged in recent years resulting in reliable strategies for the formation of spectacular self-assembled metal-ligand clusters and capsules. Main group ions have not shared in this burst of activity. In fact, ions in this part of the periodic table have largely been overlooked for use as directing elements in self-assembly reactions, despite the need for improved chelators for main group ions for a variety of applications. This review surveys our approach to developing design strategies to prepare self-assembled nanoscale supramolecular complexes containing main group ions, with a particular emphasis on supramolecular arsenic(III) coordination chemistry.

The reaction of AsCl3 with H2L (where L = a rigid dithiolate) results in the self-assembly of As2L2Cl2 supramolecular macrocycles. For ligands 4,4'-bis(mercaptomethyl)biphenyl (H2), 4,4'-bis(mercaptomethyl)-trans-stilbene (H2), and 1,4-dimethoxy-2,5-bis(mercaptomethyl)benzene (H2), the macrocyclic cavities of the resulting assemblies are large enough to host aromatic solvent molecules, as revealed by single crystal X-ray structures of the inclusion complexes. As2L2Cl(2) macrocycles form in solution as a mixture of diastereomers, but the diastereomers can be selectively crystallized and separated. Crystallization of syn- or anti-As(2)3(2)Cl2 can be controlled using host-guest interactions by the prudent choice of crystallization solvents. anti-As(2)3(2)Cl2 crystallizes exclusively from chloroform and benzene, while a [(syn-As(2)(2)Cl(2))(2).p-xylene] dimer crystallizes from p-xylene and a mixture of [(syn-As(2)3(2)Cl(2))(anti-As(2)3(2)Cl2) x toluene] and [(syn-As(2)3(2)Cl2)2 x toluene] dimers crystallize from toluene.

The As-pi interaction, in conjunction with reversible As-thiolate bond formation, is used to direct the self-assembly of dinuclear As2L2Cl2 (L = a dithiolate) macrocycles that exist as equilibrium mixtures of both syn and anti diastereomers. The diastereomeric excess of these self-assembly reactions is controlled in a predictable manner by prudent choice of different achiral, isomeric ligands. A general method for the preparation of As2L2Cl2 macrocycles is established, and strategies to control the diastereoselective self-assembly of regioisomeric macrocycles in solution and the crystalline state are described. A mechanism for the interconversion between diastereomers (a slow process on the NMR time scale) is suggested, and variable-temperature NMR spectroscopic data show that the diastereomeric excess (de) decreases with increasing temperature. anti-As2(L2,6)2Cl2 crystallizes in monoclinic space group P2(1)/n with a = 6.3949(13), b = 19.675(4), c = 10.967(2) A, beta = 106.817(3) degrees , and Z = 2. anti-As2(L1,5)2Cl2 crystallizes in monoclinic space group P2(1)/c with a = 6.813(4), b = 19.085(12), c = 10.277(6) A, beta = 107.788(10) degrees , and Z = 4. syn-As2(L1,4)2Cl2.CHCl3 crystallizes in triclinic space group P(-) with a = 19.313(4), b = 19.923(4), c = 24.508(5) A, alpha = 78.110(4) degrees , beta = 78.860(5) degrees , gamma = 89.183(5) degrees , and Z = 12. As2(L1,4)2Cl2.C6H6 crystallizes in monoclinic space group P2(1)/n with a = 10.3332(7), b = 34.375(2), c = 17.8593(12) A, beta = 98.9650(10) degrees , and Z = 8.

The syntheses and X-ray crystal structures of six new self-assembled supramolecular As and Sb-containing cryptands are described. Analysis in the context of previously reported As(2)L(3) and Sb(2)L(3) cryptands reveals that small differences in ligand geometries result in significant differences in the helicity of the complexes and the stereochemistry of the metal coordination within the assembled complexes. Additionally, a new synthetic route is described which involves exposure of reactants to vacuum to help facilitate self-assembly.