Carbonyl sulfide (COS) is hypothesized to play potential roles as a peptide coupling agent in prebiotic chemistry, and recent work harnessing the carbonic anhydrase-mediated COS hydrolysis for H2S release has led to a resurgence of interest in COS-related chemistry. Building from the importance of metal chalcogenides in bioinorganic systems and the potential of forming metal carbonyls under reducing environments, we investigated whether simple metal carbonyl compounds could be a source of COS or COSe when treated with elemental S or Se, respectively. Using the simple carbonyl compounds [TpMo(CO)3]- and [TpW(CO)3]-, we measured and quantified COS generation en route to [TpMo(S)(S4)]- and [TpW(S)3]- product formation, respectively. Highlighting the different reactivity of the selenium congener, analogous reactions with gray Se did not generate COSe. We found that [TpMo(CO)3]- was inert toward Se, and [TpW(CO)3]- reacted with Se to form the unusual triselenide-bridged product [TpW(CO)2]2Se3, which was characterized by X-ray crystallography. Taken together, these results advance our understanding of the potential role of metal carbonyl compounds in the metal-mediated interconnectivity between CO and reactive sulfur and selenium species and further differentiate reactivity profiles between sulfur and selenium motifs at the inorganic centers.

Association constant (K a) measurements provide fundamental information on host-guest interactions in supramolecular chemistry and other areas of science. Here we report the use of in situ FTIR spectroscopy to measure the K a values across three classes of host-guest complexes that involve hydrogen bonding and halogen bonding. This approach can be performed with minimal sample preparation, does not require deuterated solvents, can measure association based on changes in host or guest vibrations, and benefits from a much shorter timescale than NMR spectroscopy. Due to its fast timescale, FTIR spectroscopy also provides details on host/guest conformational changes, such as the presence of unsymmetrical host conformations that are not in the ideal binding conformation until treatment with a suitable guest. These changes would not be observable by standard time-averaged NMR titration measurements. Using this approach, we demonstrated the capabilities and challenges of this technique to investigate host-guest interactions of three anion receptors that use hydrogen or halogen bonding with both mono- and polyatomic anions. In addition to directly observing how host-guest interactions impact bonding within the individual molecules, we also demonstrate that global fitting of the FTIR spectra is an effective and robust approach to measure K a values of these host-guest complexes. We anticipate that this method will provide a new and useful approach to investigating the dynamics and specific interactions across broad areas of science.

Hydrogen sulfide (H2S) fluorescent probes are important tools for imaging and understanding H2S in biology. One significant requirement for such probes is that they are highly selective for H2S over competing analytes, which are often present at much higher levels than endogenous H2S. Different approaches have been used to generate selective H2S probes, and recently, highly selective probes using 2-thiophene esters have been reported. We report here that in contrast to prior reports, thiophene ester probes are not selective for H2S but rather report on both biothiols and esterase activity. We do demonstrate, however, that the rate of reactivity toward H2S can be enhanced by incorporating an ortho aldehyde, leading to an 85-fold rate enhancement. We anticipate that this work will further clarify effective approaches for selective H2S detection and also advance strategies for improving the selectivity of electrophilic probes for H2S and other related nucleophiles.

H2S and NO are physiologically important signaling molecules with complex roles in biology and intermolecular crosstalk. Although these species are often referred to as neutral on paper, they are primarily found in anionic and/or oxidized forms in aerobic solutions as HS- or NO2-/NO3-, respectively. Despite the prominence of these anions in biology, particularly HS- and NO2-, few investigations have focused on the molecular recognition and reversible binding of these important species. Using a library of imidazolium receptors with C-H hydrogen bonding interactions, we investigate the influences on binding affinity through modulation of charge, multiplicity, and preorganization, while also investigating how anion volume impacts binding. These factors are probed by solution-state titration experiments and solid-state X-ray crystallographic data showing the specific molecular interactions involved in guest binding. Both solution-state NMR and solid-state X-ray crystallography support the importance and abundance of C-H···X- interactions in facilitating guest binding as well as conformational changes upon anion recognition.

S/N hybrid species, such as perthionitrite (SSNO-) and thionitrite (SNO-), play intricate roles in nitric oxide (NO•) and hydrogen sulfide (H2S) biological signaling and transport pathways. Despite this emerging significance, the fundamental reactivities of these species remain largely unexplored. In particular, a significant gap remains in understanding how these S/N hybrid species react with redox active metal centers. Building from this gap, we report here the reactivity of SSNO- and SNO- toward tripodal Fe2+ complex [Fe(3CF3-baTren)]- (1) and examine the associated reactive nitrogen and sulfur species output pathways from these reactions using both spectroscopic and chemical trapping techniques. Specifically, we observe that complex 1 facilitates S-N bond homolysis of SSNO- to give {Fe-NO}7 complex [Fe(3CF3-baTren)(NO)]- (2) and polysulfide radicals, whereas SNO- reacts with 1 to undergo S-centered reduction to give S2- and NO•. Taken together, these results advance our understanding of how small molecule S/N hybrids react with redox active metal centers and may contribute to metal nitrosyl formation.

Hydrogen sulfide (H2S) and other reactive sulfur species are important small molecules with biological significance. In addition to common reactive sulfur species like H2S, polysulfides, and persulfides, both carbonyl sulfide (COS) and carbon disulfide (CS2) have been postulated to be potential sources of reduced sulfur. To better understand this possible connection, we demonstrate that H2S can be converted to COS and CS2 by reaction with simple organic carbonate and thiocarbonate electrophiles, respectively.

Cucurbit[n]urils (CB[n]s) are cyclic macrocycles with rich host-guest chemistry and can bind a variety of guests, often with high association constants. In many cases, guest binding in CB[n]s results in structural deformations in the host to accommodate guests of different sizes and shapes. Unfortunately, measuring such deformations has remained a major challenge, with only a handful of manual estimations reported in the literature. To address this challenge and to allow for the simple measurement and analysis of CB[n] deformations both in the presence and absence of guests, we have developed the public program ElliptiCB[n], which is available on GitHub, that provides a robust and automated method for measuring the elliptical deformations in CB[n] hosts. We outline the development and validation of this approach, apply ElliptiCB[n] to measure to the ellipticity of the 1113 available CB[n] structures from the Cambridge Structural Database (CSD), and directly investigate the structural deformations of CB[5], CB[6], CB[7], CB[8], and CB[10]. We also report the general landscape of accessible CB[n] elliptical deformations and compare ellipticity distributions across CB[n] hosts and host-guest complexes. We found that in almost all cases guest binding significant impacts the distribution of host ellipticity distributions and that ellipticity distributions are dissimilar across host-guest complexes of differently sized CB[n]s. We anticipate that this work will provide not only be a useful approach for understanding of the flexibility of CB[n] hosts but will also enable future measurement and standardization of ellipticity measurements of CB[n] X-ray and/or computational data.

Hydrogen sulfide (H2S) is not only a well-established toxic gas but also an important small molecule bioregulator in all kingdoms of life. In contemporary biology, H2S is often classified as a "gasotransmitter," meaning that it is an endogenously produced membrane permeable gas that carries out essential cellular processes. Fluorescent probes for H2S and related reactive sulfur species (RSS) detection provide an important cornerstone for investigating the multifaceted roles of these important small molecules in complex biological systems. A now common approach to develop such tools is to develop "activity-based probes" that couple a specific H2S-mediated chemical reaction to a fluorescent output. This Review covers the different types of such probes and also highlights the chemical mechanisms by which each probe type is activated by specific RSS. Common examples include reduction of oxidized nitrogen motifs, disulfide exchange, electrophilic reactions, metal precipitation, and metal coordination. In addition, we also outline complementary activity-based probes for imaging reductant-labile and sulfane sulfur species, including persulfides and polysulfides. For probes highlighted in this Review, we focus on small molecule systems with demonstrated compatibility in cellular systems or related applications. Building from breadth of reported activity-based strategies and application, we also highlight key unmet challenges and future opportunities for advancing activity-based probes for H2S and related RSS.

Hydrogen sulfide (H 2 S) and nitric oxide (NO) are important gaseous biological signaling molecules that are involved in complex cellular pathways. A number of physiological processes require both H 2 S and NO, which has led to the proposal that different H 2 S/NO⋅ crosstalk species, including thionitrite (SNO − ) and perthionitrite (SSNO − ), are responsible for this observed codependence. Despite the importance of these S/N hybrid species, the reported properties and characterization, as well as the fundamental pathways of formation and subsequent reactivity, remain poorly understood. Herein we report new experimental insights into the fundamental reaction chemistry of pathways to form SNO − and SSNO − , including mechanisms for proton-mediated interconversion. In addition, we demonstrate new modes of reactivity with other sulfur-containing potential crosstalk species, including carbonyl sulfide (COS).

Hydrogen sulfide is an important reactive sulfur species that is involved in many biological functions, and H2S imbalances have been indicated as a potential biomarker for various diseases. Different H2S donors have been developed to deliver H2S directly to biological systems, but few reports include donors with optical responses that allow for tracking of H2S release. Moreover, donor systems that use the same chemistry to deliver H2S across a palette of fluorescent responses remain lacking. Here we report five thiol-activated fluorescence turn-on COS/H2S donors that utilize blue, yellow, orange, red, and near infrared-emitting dyes functionalized with an H2S-releasing sulfenyl thiocarbonate scaffold. Upon treatment with thiols, each donor provides a fluorescence turn-on response (3–310-fold) and high H2S release efficiencies (>60%). Using combined electrode and fluorescence experiments, we directly correlate the measured H2S release with the fluorescence response. All donors are biocompatible and release H2S in live cell environments. In addition, we demonstrate that the NIR donor allows for H2S release tracking after subcutaneous injection in live rats, which to the best of our knowledge is the first in vivo tracking of fluorogenic H2S release in non-transparent organisms.

Persulfides (RSSH) are biologically important reactive sulfur species that are endogenously produced, protect key cysteine residues from irreversible oxidation, and are important intermediates during different enzymatic processes. Although persul-fides are stronger nucleophiles than their thiol counterparts, persulfides can also act as electrophiles in their neutral, proto-nated form in specific environments. Moreover, persulfides are electrophilic at both sulfur atoms, and reaction with a thiolate can lead to either H2S release with disulfide formation or alternatively result in transpersulfidation. Despite the broad ac-ceptance of these reaction pathways, the specific properties that control whether persulfides react through the H2S releasing or transpersulfidation pathway remains elusive. Herein, we use a combined computational and experimental approach to directly investigate the reactivity between persulfides and thiols to answer these questions. Using DFT calculations, we demonstrate that increasing steric bulk or electron withdrawal near the persulfide can shunt persulfide reactivity through the transpersulfidation pathway. Building from these insights, we use a persulfide donor and TME-IAM trapping agent to experi-mentally monitor and measure transpersulfidation from a bulky penicillamine-based persulfide to a cysteine-based thiol, which to the best of our knowledge is the first direct observation of transpersulfidation between low molecular weight spe-cies. Taken together, these combined approaches highlight how the properties of persulfides are directly impacted by local environments, which has significant impacts in understanding the complex chemical biology of these reactive species.

Persulfides (RSS–) are ubiquitous source of sulfides (S2–) in biology, and interactions between RSS– and bioinorganic metal centers play critical roles in biological hydrogen sulfide (H2S) biogenesis, signaling, and catabolism. Here we report the use of contact-ion stabilized [Na(15-crown-5)][tBuSS] (1) as a simple synthon to access rare metal alkyl persulfide complexes and to investigate the reactivity of RSS– with transition metal centers to provide insights into metal thiolate persulfidation includ-ing the fundamental difference between alkyl persulfides and alkyl thiolates. Reaction of 1 with [CoII(TPA)(OTf)]+ afforded the η1-alkyl persulfide complex [CoII(TPA)(SStBu)]+ (2), which was characterized by X-ray crystallography, UV-vis spectros-copy, and Raman spectroscopy. RSS– coordination to the Lewis acidic Co2+ center provided additional stability to the S–S bond as evidenced by a significant increase in the Raman stretching frequency for 2 (vS–S = 522 cm–1, ΔvS–S = 66 cm–1). The effect of persulfidation on metal center redox potentials was further elucidated using cyclic voltammetry, in which the Co2+ → Co3+ oxidation potential of 2 (Ep,a = +89 mV vs SCE) is lowered by nearly 700 mV when compared to the corresponding thiolate complex [CoII(TPA)(StBu)]+ (3) (Ep,a = +818 mV vs SCE), despite persulfidation being an oxidative post-translational modifica-tion. Reactivity of 2 toward reducing agents including PPh3, BH4–, and biologically relevant thiol reductant DTT led to differ-ent S2– output pathways including formation of a dinuclear 2Co-2SH complex [CoII2(TPA)2(µ2-SH)2]2+(4).

H2S is a physiologically important signaling molecule with complex roles in biology and exists primarily as HS- at physiological pH. Despite this anionic character, few investigations have focused on the molecular recognition and reversible binding of this important biological anion. Using a series of imidazole and imidazolium host molecules, we investigate the role of preorganization and charge on HS- binding. Using a macrocyclic bis-imidazolium receptor, we demonstrate the unexpected 2:1 host-guest binding of HS-, which was characterized both in solution and by X-ray crystallography. To the best of our knowledge, this is the first example of this binding stoichiometry for HS- binding. Moreover, the short C-H···S distances of 2.53, 2.54, 2.76, and 2.79 Å are well within the sum of the van der Waals radii of the interacting atoms, which is consistent with strong C-H···S interactions.

Reactive sulfur species (RSS) and reactive selenium species (RSeS) play integral roles in hydrogen sulfide (H2S) and hydrogen selenide (H2Se) biological signaling pathways, and dichalcogenide anions are proposed transient intermediates that facilitate a variety of biochemical transformations. Herein we report the selective synthesis, isolation, spectroscopic and structural characterization, and fundamental reactivity of persulfide (RSS-), perselenide (RSeSe-), thioselenide (RSSe-), and selenosulfide (RSeS-) anions. The isolated chalcogenides do not rely on steric protection for stability and have steric profiles analogous to cysteine (Cys). Simple reduction of S8 or Se by potassium benzyl thiolate (KSBn) or selenolate (KSeBn) in the presence of 18-crown-6 afforded [K(18-crown-6)][BnSS] (1), [K(18-crown-6)][BnSeSe] (2), [K(18-crown-6][BnSSe] (3), and [K(18-crown-6][BnSeS] (4). The chemical structure of each dichalcogenide was confirmed by X-ray crystallography and solution-state 1H, 13C, and 77Se NMR spectroscopy. To advance our understanding of the reactivity of these species, we demonstrated that reduction of 1-4 by PPh3 readily generates E═PPh3 (E: S, Se), and reduction of 1, 3, and 4 by DTT readily produces HE-/H2E. Furthermore, 1-4 react with CN- to produce ECN-, which is consistent with the detoxifying effects of dichalcogenide intermediates in the Rhodanese enzyme. Taken together, this work provides new insights into the inherent structural and reactivity characteristics of dichalcogenides relevant to biology and advances our understanding of the fundamental properties of these reactive anions.

Hydrogen sulfide (H2S) is an important biological mediator across all kingdoms of life and plays intertwined roles in various disciplines, ranging from geochemical cycles to industrial processes. A common need across these broad disciplines is the ability to detect and measure H2S in complex sample environments. This Perspective focuses on key advances and opportunities for H2S detection and quantification that are relevant to chemical biology. Specifically, we focus on methods for H2S detection and quantification most commonly used in biological samples, including activity-based H2S probes, the methylene blue assay, the monobromobimane assay, and H2S-sensitive electrode measurements. Our goal is to help simplify what at first may seem to be an overwhelming array of detection and measurement choices, to articulate the strengths and limitations of individual techniques, and to highlight key unmet needs and opportunities in the field.

Carbonyl sulfide (COS) is implicated in prebiotic chemistry, and recent work on COS/H2S donors has invigorated COS chemistry. We demonstrate that [TpM(CO)3]- (M=Mo,W) react with S8 to form COS, but form [TpW(CO)2]2Se3 not COSe upon reaction with Se. These results advance the metal-mediated interconnectivity of CO and reactive S/Se species.

Hydrogen selenide (H2Se) is a possible bioregulator, potential gasotransmitter, and important precursor in biological organoselenium compound synthesis. Early tools for H2Se research have benefitted from available mechanistic understanding of analogous small molecules developed for detecting or delivering H2S. A now common approach for H2S delivery is the use of small molecule thiocarbamates that can be engineered to release COS, which is quickly converted to H2S by carbonic anhydrase. To expand our understanding of the chemical underpinnings that enable H2Se delivery, we investigated whether selenocarbamates undergo similar chemistry to release carbonyl selenide (COSe). Using both light- and hydrolysis-activated systems, we demonstrate that unlike their lighter thiocarbamate congeners, selenocarbamates release H2Se directly with concomitant isocyanate formation rather than by the intermediate release of COSe. This reaction mechanism for direct H2Se release is further supported by computational investigations that identify a ΔΔG‡ ∼ 25 kcal mol-1 between the H2Se and COSe release pathways in the absence of protic solvent. This work highlights fundamentally new approaches for H2Se release from small molecules and advances the understanding of reactivity differences between reactive sulfur and selenium species.

Hydrosulfide (HS−) is the conjugate base of gasotransmitter hydrogen sulfide (H2S) and is a physiologically-relevant small molecule of great interest in the anion sensing community. However, selective sensing and molecular recognition of HS− in water remains difficult because, in addition to the diffuse charge and high solvation energy of anions, HS− is highly nucleophilic and readily oxidizes into other reactive sulfur species. Moreover, the direct placement of HS− in the Hofmeister series remains unclear. Supramolecular host–guest interactions provide a promising platform on which to recognize and bind hydrosulfide, and characterizing the placement of HS− in the Hofmeister series would facilitate the future design of selective receptors for this challenging anion. Few examples of supramolecular HS− binding have been reported, but the Sindelar group reported HS− binding in water using bambus[6]uril macrocycles in 2018. We used this HS− binding platform as a starting point to develop a chemically-sensitive field effect transistor (ChemFET) to facilitate assigning HS− to a specific place in the Hofmeister series. Specifically, we prepared dodeca-n-butyl bambus[6]uril and incorporated it into a ChemFET as the HS− receptor motif. The resultant device provided an amperometric response to HS−, and we used this device to measure the response of other anions, including SO42−, F−, Cl−, Br−, NO3−, ClO4−, and I−. Using this response data, we were able to experimentally determine that HS− lies between Cl− and Br− in the Hofmeister series, which matches recent theoretical computational work that predicted a similar placement. Taken together, these results highlight the potential of using molecular recognition coupled with ChemFET architectures to develop new approaches for direct and reversible HS− detection and measurement in water and further advance our understanding of different recognition approaches for this challenging anion.

Several phosphaquinolinone derivatives have been synthesized and characterized to explore their usefulness in the realm of cell imaging. Solution-state photophysical properties in both aqueous and organic solutions were collected for these derivatives. Additionally, CCK-8 cell viability assays and fluorescent imaging in HeLa cells incubated with the new heterocyclic derivatives show evidence of favorable cell permeability, cell viability, and moderate intracellular localization when appended with the well-known morpholine targeting motif.

Elemental sulfur (S8) may contribute to sulfane sulfur (S0) storage in biological systems. We demonstrate that surfactants can solubilize S8 in water and promote S8 reduction to H2S by thiols. Moreover, anionic and cationic surfactants interact differently with intermediate S0 carriers, highlighting how specific hydrophobic microenvironments impact reactive sulfur species.