The understanding of selectivity in reactions exhibiting nonstatistical dynamics is impeded by the limitations of trajectory studies with regard to nuclear quantum effects, especially tunneling. We described here the use of ring-polymer molecular dynamics (RPMD) to account for an unusual regiochemical isotope effect on the regioselectivity of hydroborations of alkenes with BH3/BD3. RPMD is able to account for the experimental observation, while statistical approaches and classical trajectories fail. The combination of experiment and RPMD trajectories suggests that tunneling in the initial collision of reactants is the major source of the nonstatistical selectivity.

We report a new class of carboplatin-TFO hybrid that incorporates a bifunctional alkyne–amine nucleobase monomer called AP-C3-dT that enables dual ‘click’ platinum( ii ) drug conjugation and thiazole orange fluorophore coupling.

Abstract Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we have developed reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3´-OH is replaced by an ethanoic acid group, were synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.

Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.

The initial energy in a reactive intermediate is derived from the transition state before the intermediate but can affect selectivity after the intermediate. In this way an observable selectivity can report on a prior, kinetically hidden mechanistic step. This new type of mechanistic probe is demonstrated here for the oxidation of 1-methylcyclobutanol by phthaloyl peroxide/Bu4N+Br-, and it supports a hypobromite chain mechanism in place of the previously proposed hydrogen atom transfer mechanism.

13C kinetic isotope effects (KIEs) for the photoredox-promoted [2 + 2] cycloaddition of enones were determined in homocoupling and heterocoupling examples. The only significant KIEs were observed at the β carbon, indicating that Cβ-Cβ bond formation is irreversible. However, these KIEs were much lower than computational predictions, suggesting that product selectivity is determined in part by a step prior to Cβ-Cβ bond formation. The results are explained as arising from a competition between C-C bond formation and electron exchange between substrate alkenes. This idea is supported by a relatively small substituent effect on substrate selectivity. The possible rates for electron transfer and bond-forming steps are analyzed, and the competition appears plausible, particularly if the mechanism involves a complex between reduced and neutral enone molecules.

Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of PtII -TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA-intercalating fluorophore-into PtII -TFOs constructs, enhanced target binding and discrimination between target and off-target sequences was achieved.

A common question I receive when talking with graduate students is how to know when an article is ready to be submitted to an academic journal for publication. This seemingly simple question is fraught with complexity. Often, the desire to publish a complete, fully supported, and new story (the difficult-to-achieve 'perfect' story) is at conflict with the need to publish on a reasonable timescale often dictated by external (or even internal) deadlines. In this TrendsTalk, we ask several scientists about key advice that they give to their trainees.

In the field of nucleic acid therapy there is major interest in the development of libraries of DNA‐reactive small molecules which are tethered to vectors that recognize and bind specific genes. This approach mimics enzymatic gene editors, such as ZFNs, TALENs and CRISPR‐Cas, but overcomes the limitations imposed by the delivery of a large protein endonuclease which is required for DNA cleavage. Here, we introduce a chemistry‐based DNA‐cleavage system comprising an artificial metallo‐nuclease (AMN) that oxidatively cuts DNA, and a triplex‐forming oligonucleotide (TFO) that sequence‐specifically recognises duplex DNA. The AMN‐TFO hybrids coordinate Cu II ions to form chimeric catalytic complexes that are programmable – based on the TFO sequence employed – to bind and cut specific DNA sequences. Use of the alkyne‐azide cycloaddition click reaction allows scalable and high‐throughput generation of hybrid libraries that can be tuned for specific reactivity and gene‐of‐interest knockout. As a first approach, we demonstrate targeted cleavage of purine‐rich sequences, optimisation of the hybrid system to enhance stability, and discrimination between target and off‐target sequences. Our results highlight the potential of this approach where the cutting unit, which mimics the endonuclease cleavage machinery, is directly bound to a TFO guide by click chemistry.

Large intramolecular 13C kinetic isotope effects (KIEs) for the di-π-methane rearrangement of benzobarrelene fit with statistical expectations from heavy-atom tunneling when a low-energy sensitizer is employed, but much lower KIEs are observed with higher-energy sensitizers. These results in combination with trajectory studies suggest that the excess vibrational energy available from triplet energy transfer leads to hot and nonstatistical dynamics in the rearrangement.

Additions of acids to 1,3-dienes are conventionally understood as involving discrete intermediates that undergo an ordinary competition between subsequent pathways to form the observed products. The combined experimental, computational, and dynamic trajectory study here suggests that this view is incorrect, and that solvation dynamics plays a critical role in the mechanism. While implicit solvent models were inadequate, QM/QM' trajectories in explicit solvent provide an accurate prediction of the experimental selectivity in the addition of HCl to 1,3-pentadiene. Trajectories initiated from a protonation saddle point on the potential of mean force surface are predominantly unproductive due to a gating effect of solvation that allows diene protonation only when the incipient ion pair is neither too solvent-stabilized nor too little. Protonation then leads to relatively unsolvated ion pairs, and a majority of these collapse rapidly to the 1,2-product, without barrier and without achieving equilibrium solvation as intermediates. The remainder decay slowly, at a rate consistent with equilibrium solvation as true intermediates, affording a mixture of addition products. Overall, an accurate description of the nature and pathway selectivity of the ion pair intermediates in carbocation reactions must allow for species lacking equilibrium solvation. Potential reinterpretations of a series of historically notable observations in carbocation reactions are discussed.

The carboborative ring contraction of cyclohexenes exhibits an abnormal selectivity pattern in which a formally concerted double-migration gives rise to predominant but not exclusive inversion products. In dynamic trajectories, the inversion and retention products are formed from the same transition state, and the trajectories accurately account for the experimental product ratios. The unusual origin of the selectivity is the dynamically retained nonequivalence of newly-formed versus preexisting bonds after the first bond migration.

Díaz-Urrutia and Ott (Reports, 22 March 2019, p. 1326) report a selective conversion of methane to methanesulfonic acid that is proposed to occur by a cationic chain reaction in which CH 3 + adds to sulfur trioxide (SO 3 ) to form CH 3 –S(O) 2 O + . This mechanism is not plausible because of the solvent reactivity of CH 3 + , the non-nucleophilicity of the sulfur atom of SO 3 , and the high energy of CH 3 –S(O) 2 O + .

We have synthesised a range of thiazole orange (TO) functionalised oligonucleotides for nucleic acid detection in which TO is attached to the nucleobase or sugar of thymidine. The properties of duplexes between TO-probes and their DNA and RNA targets strongly depend on the length of the linker between TO and the oligonucleotide, the position of attachment of TO to the nucleotide (major or minor groove) and the mode of attachment of thiazole orange (via benzothiazole or quinoline moiety). This information can be used to design probes for detection of target nucleic acids by fluorescence or duplex melting. With cellular imaging in mind we show that 2 '-OMe RNA probes with TO at the 5-position of uracil or the 2 '-position of the ribose sugar are particularly effective, exhibiting up to 44-fold fluorescence enhancement against DNA and RNA, and high duplex stability. Excellent mismatch discrimination is achieved when the mispaired base is located adjacent to the TO-modified nucleotide rather than opposite to it. The simple design, ease of synthesis and favourable properties of these TO probes suggest applications in fluorescent imaging of DNA and RNA in a cellular context.

Any long-lived chemical structure in solution is subject to statistical energy equilibration, so the history of any specific structure does not affect its subsequent reactions. This is not true for very short-lived intermediates because energy equilibration takes time. Here, this idea is applied to achieve the ‘energy labelling’ of a reactive intermediate. The selectivity of the ring-opening α-cleavage reaction of the 1-methylcyclobutoxy radical is found here to vary broadly depending on how the radical was formed. Reactions that provide little excess energy to the intermediate lead to a high selectivity in the subsequent cleavage (measured as a kinetic isotope effect), whereas reactions that provide more excess energy to the intermediate exhibit a lower selectivity. Accounting for the expected excess energy allows the prediction of the observed product ratios and, in turn, the product ratios can be used to determine the energy present in an intermediate.

Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG‡ = 27.1 ± 0.1 kcal mol-1 at 90 °C, ΔH‡ = 13.8 ± 1.0 kcal mol-1, and ΔS‡ = -37 ± 3 cal mol-1 K-1, measured over the range 70-90 °C. Carbon kinetic isotope effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ+ of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.