Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin‐mediated Giese reactions were nearly forty years ago. With the global recognition of organometallic photocatalysts for the mild and tunable generation of carbon‐centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox‐mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon‐centered radical intermediates that can engage in radical conjugate addition processes.

A general method for the N-arylation of sulfamides with aryl bromides is described.The protocol leverages a dual-catalytic system of nickel and a photoexcitable iridium complex and proceeds at room temperature under visible light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through the reaction untouched. Thereby, this method complements known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.

Alcohol-anchored sulfamate esters guide the alkylation of tertiary and secondary aliphatic C(3)−H bonds. The transformation proceeds directly from N−H bonds with a catalytic oxidant, a contrast to prior methods which have required preoxidation of the reactive nitrogen center, or employed stoichiometric amounts of strong oxidants to obtain the sulfamyl radical. These sulfamyl radicals template otherwise rare 1,6-hydrogen-atom transfer (HAT) processes via seven-membered ring transition states to enable C(3)−H functionalization during Giese reactions.N itrogen-centered radicals are an important and versatile class of chemical intermediates. 1 Yet, nitrogen-centered radicals remain underutilized, as most methods for their generation rely on harsh conditions to oxidize the nitrogen center. Recently, photocatalytic strategies have been developed as mild processes to form nitrogen-centered radicals; 2−6 however, only amides, carbamates, and sulfonamides have served as precursors to neutral nitrogen-centered radicals. 4−6 These groups template position-selective C−H functionalization technologies, transforming C(4)−H bonds through 1,5-HAT processes (Scheme 1A). 7 In contrast, sulfamate esters guide functionalization to C(3)−H centers through otherwise rare 1,6-HAT processes (Scheme 1B), providing complementary positional selectivity to established processes. 8−16 As a complement to known guided methods, sulfamate esters are attractive directing groups because they derive from alcohols, which are ubiquitous in biologically active small molecules. To date, protocols templated by sulfamate ester substrates require preoxidation of the reactive nitrogen center, or the use of strong stoichiometric oxidants to access nitrogen-centered sulfamyl radicals. 14,15 As such, a strategy to facilitate sulfamyl radical formation directly from N−H bonds under mild conditions would enhance the substrate tolerance of these directing motifs, and could also enable previously unrealized synthetic disconnections. 17,18 Herein disclosed is the first catalytic process to access free sulfamyl radicals directly from N−H bonds. 19 These sulfamyl radicals have been engaged in Giese reactions, in the only examples of C(3)−H alkylation reactions guided by alcohol surrogates (Scheme 1C, 1 → 2).At the outset of these investigations, we sought conditions that would facilitate oxidation of sulfamate ester 1a to sulfamyl radical 3a. We envisioned that this could occur through an initial deprotonation to provide sulfamate ester anion 4a. Anion 4a could undergo single electron oxidation to generate sulfamyl radical 3a, with concurrent reduction of the excited iridium catalyst 6a (Scheme 2). Consistent with this proposal, in acetonitrile, sodiated 5-methylhexyl N-tert-butyl sulfamate ester anion 4a has a half-peak potential (E p/2 ) of +0.753 V

A general method is described for the coupling of (hetero)­aryl bromides with O-alkyl sulfamate esters. The protocol relies on catalytic amounts of nickel and photoexcitable iridium complexes and proceeds under visible light irradiation at ambient temperature. This technology engages a broad range of simple and complex O-alkyl sulfamate ester substrates under mild conditions. Furthermore, it is possible to avoid undesirable N-alkylation, which was found to plague palladium-based protocols for N-arylation of O-alkyl sulfamate esters. These investigations represent the first use of sulfamate esters as nucleophiles in transition metal-catalyzed C–N coupling processes.

One of the first environmental cues sensed by a microbe as it enters a human host is an upshift in temperature to 37°C. In this dynamic timepoint analysis, we demonstrate that this environmental transition rapidly signals a multitude of gene expression changes in Escherichia coli . Bacteria grown at 23°C under aerobic conditions were shifted to 37°C and mRNA expression was measured at timepoints after the shift to 37°C (t=0.5, 1, and 4 hours). The first hour is characterized by a transient shift to anaerobic respiration strategies and stress responses, particularly acid resistance, indicating that temperature serves as a sentinel cue to predict and prepare for various niches within the host. The temperature effects on a subset of stress response genes were shown to be mediated by RpoS, directly correlated with RpoS, DsrA and RprA levels, and increased acid resistance was observed that was dependent on 23°C growth and RpoS. By 4 hours, gene expression shifted to aerobic respiration pathways, decreased stress responses, coupled with increases in genes associated with biosynthesis (amino acid, nucleotides), iron uptake, and host defense. ompT , a gene that confers resistance to antimicrobial peptides, was highly thermoregulated and with a pattern conserved in enteropathogenic and uropathogenic E. coli . An immediate decrease in curli gene expression concomitant with an increase in flagellar gene expression implicates temperature in this developmental decision. Together, our studies demonstrate that temperature signals a reprogramming of gene expression immediately upon an upshift that may predict, prepare, and benefit survival of the bacterium within the host. IMPORTANCE: As one of the first cues sensed by the microbe upon entry into a human host, understanding how bacteria like E. coli modulate gene expression in response to temperature improves our understanding of how bacteria immediately initiate responses beneficial to survival and colonization. For pathogens, understanding the various pathways of thermal regulation could yield valuable targets for anti-infective chemotherapeutic drugs or disinfection measures. In addition, our data provide a dynamic examination of the RpoS stress response, providing genome-wide support for how temperature impacts RpoS through changes in RpoS stability and modulation by small regulatory RNAs.

A general method for the <i>N</i>-arylation of sulfamides with aryl bromides is described. The protocol leverates a dual-catalytic system of nickel and a photoexcitable iridium complex and proceeds at room temperature under visible light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through the reaction untouched. Thereby, this method complements known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.

10. Alkoxyl radicals enable 1,5-HAT processes to generate carbon-centered radicals 21310 11. Direct hydrogen-atom abstraction of non-reactive C(sp 3 )ÀHb onds generates carbon-centered radicals 21312 12. Summary and Outlook 21313 Scheme 1. Until recently,most Giese reactions relied on tin hydride, or tin hydride and AIBN. Conditions were tuned to minimizep otentially competitive off-pathwayr eactions.

Background: Immunoassay (IA) measurements of thyroid hormones have previously given inaccurate results of triiodothyronine (T3), free triiodothyronine (FT3), and free thyroxine (FT4) when concentrations of TBG are low. We evaluate the hypothesis that abnormal concentrations of specific binding proteins (BPs) affect IA measurements and provide results which might misguide the diagnosis and treatment of patients. This study assesses IAs for the measurement of T3, FT3, and cortisol when levels of TBG and CBG are high or low. Comparisons are made between IA and LC-MS/MS. Methods: Serum or plasma samples with high (>95th percentile, n = 25) or low (<5th percentile, n = 27) concentrations of BP were collected. The concentrations of T3, FT3, and cortisol were measured by validated IA and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Spearman correlation and Wilcoxon matched-pairs signed rank analyses were used to compare the two methods. Results: When TBG levels are <5th percentile, the differences between the IA and LC-MS/MS results for T3 and FT3 are statistically significant (T3, p = 0.0011; FT3, p = 0.0003). When CBG levels are >95th percentile, the difference between the IA and LC-MS/MS measurements of cortisol is statistically significant ( p = <0.0001). Conclusion: Abnormal BP concentrations appear to affect the accuracy of IA measurements of T3, FT3, and cortisol. The population of patients with either high or low levels of BPs is significant. Our samples reflect that 65% of women aged between 15 and 49 years are taking oral contraceptives in the US, and thus have elevated levels of BPs. In this group, IA results for cortisol are falsely low. Our samples reflect that patients with protein losing diseases have low BP concentrations. Among a group with renal complications, IA measurements of T3 are overestimated, while those of FT3 are underestimated. Are the Food and Drug Administration and diagnostic companies adequately assessing the accuracy of IA tests?