Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guaninecytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, - stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.

Cu(i) carbenes derived from α-diazocarbonyl compounds lead to selective alkylation of the O6 position in guanine (O6-G) in mono- and oligonucleotides.

DNA-encoded libraries (DELs) have generated recent interest due to their ability to provide new small molecule ligands for pharmaceutically important proteins. The chemical diversity of DELs determines their ability to provide potent, novel, and drug-like chemical matter, and DEL chemical diversity is limited by the scope of DNA-compatible chemical reactions. Herein, the one-pot three-component Van Leusen chemistry is applied to DEL synthesis, providing the first reported DNA-compatible method to generate novel highly functionalized imidazoles.

Herein we provide a generalizable method for the cost-effective synthesis of thousands of building blocks (BBs) employing DNA-incompatible chemistries. The ability to produce large numbers of crude products via solid-phase synthesis has existed for decades; however, our work demonstrates a practical use of such crude reaction mixtures and employs DNAconjugation to simultaneously encode, purify, and rapidly analyze the desired products. This workflow generated sp 3 -rich BBs that could be encoded by DNA in a high-throughput manner.

We show here that copper carbenes generated from diazo acetamides alkylate single RNAs, mRNAs, or pools of total transcriptome RNA, delivering exclusively alkylation at the O6 position in guanine (O6G). Although the reaction is effective with free copper some RNA fragmentation occurs, a problem we resolve by developing a novel water-stable copper N-heterocyclic carbene complex. Carboxymethyl adducts at O6G are known mutagenic lesions in DNA but their relevance in RNA biochemistry is unknown. As a case-in-point we re-examine an old controversy regarding whether O6G damage in RNA is susceptible to direct RNA repair.

Abstract. Although stereoselectivity is often the focus of ligand optimizations in catalysis, ligand modularity can be used to control many other properties of catalysts. For example solubility, amenability to purification, and steric shielding of sensitive catalytic intermediates are all important, but seldom appreciated, functions of ligands. We describe a brief and modular approach to various homo-and heteroleptic lantern-type rhodium(II) complexes and perform benchmarking studies with the new catalysts in common rhodium(II)-catalysed reactions. We demonstrate the power of ligand modularity by creating catalysts customized for aqueous catalysis or for applications in chemical biology.Keywords: Rhodium; Carboxylate Ligands; C-H activation; Fluorescent probes; Water chemistryWe became interested in tethered bis-dicarboxylate rhodium(II) complexes in the context of our recent studies on metal-carbenoid based nucleic acid alkylation. [1] To further develop this technology we needed a set of rhodium(II) complexes with stable and modular ligands that still performed well in typical rhodium(II)-catalyzed reactions, particularly in water. Most rhodium complexes are highly insoluble in water and not readily amenable to modification. [2] We settled on the tethered bis-carboxylate structure because we thought its increased stability, [3] as well as its potential to intercalate DNA, [4] could deliver performance improvements in comparison with Rh2(OAc)4. The ligand introduced by Du Bois and co-workers [5] was chosen as a starting scaffold but two major problems prompted us to change tack: first, creating a library of ligands proved synthetically cumbersome and second, controlling mono-versus double-substitution in the rhodium carboxylates was unpredictable. Inspired by previous work from Bonar-Law in creating dirhodiumbased metal-organic architectures, [6] we examined dicarboxylate ligands derived from 1,3-benzenediols (see Scheme 1). This construct maintains the essential structural features of the espino ligand, but has the advantage of modularity since numerous 1,3-benzenediol derivatives are commercially available.Moreover, since Bonar-Law used these dicarboxylates to create well-defined supramolecular objects the coordination of each ligand needed to be precisely controlled, providing valuable information for our own studies. Scheme 1. Modular approach towards mono-and bissubstituted rhodium(II) complexes. See the ESI pages S2-S6 and S14-S19 for detailed protocols.The syntheses of the various homo-and heteroleptic rhodium(II) complexes we have prepared are shown in Scheme 1. Using the conditions developed by BonarLaw the monobiscarboxylate complex 1 is obtained in 60% yield after three hours in N,N-dimethylaniline. However, for ligands with electron withdrawing groups at C5 (10b-d) milder conditions were necessary: Rh2(OAc)2(TFA)2 in DCE at 60-70°C with small amounts of EtOAc as co-solvent led to acceptable yields (31% for 2, 27% for 3, and 35% for

We report here the synthesis and catalytic evaluation in DNA alkylation of a series of water‐soluble copper complexes bearing N‐heterocyclic carbene (NHC) ligands. The NHC ligands were chosen to cover the gamut of commonly used scaffold variations, but in many cases, copper complexes could not be obtained or were unstable. Nevertheless, we identified several complexes that were both stable and catalytically active. Our studies provide guidance and starting scaffolds for any researchers interested in aqueous copper(I) catalysis. A key practical aspect of our findings is that azide‐bearing copper‐NHC complexes are excellent substrates for the azide‐alkyne cycloaddition, which allows late‐stage tailoring of the copper complexes.

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