Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice.

Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.

Chronic demyelination and myelin repair after spinal cord injury in mice: A potential link for glutamatergic axon activity.

Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons. Results reveal peak in remyelination occurs during the 3rd mpi, and that myelin generation continues for at least 6 mpi. Further, motor evoked potentials significantly increased during peak remyelination, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination, nodal protein spreading and Nav1.2 upregulation, were also present chronically after SCI. Nav1.2 was expressed through 10 wpi and nodal protein disorganization was detectable throughout 6 mpi suggesting chronic demyelination, which was confirmed with EM. Thus, demyelination may continue chronically, which could trigger the long-term remyelination response. To examine a potential mechanism that may initiate post-injury myelination, we show that OPC processes contact glutamatergic axons in the injured spinal cord in an activity-dependent manner. Notably, these OPC/axon contacts were increased 2-fold when axons were activated chemogenetically, revealing a potential therapeutic target to enhance post-SCI myelin repair. Collectively, results show the surprisingly dynamic nature of the injured spinal cord over time and that the tissue may be amenable to treatments targeting chronic demyelination.

Engineering Flexible Metal-Phenolic Networks with Guest Responsiveness via Intermolecular Interactions.

Flexible metal-organic materials are of growing interest owing to their ability to undergo reversible structural transformations under external stimuli. Here, we report flexible metal-phenolic networks (MPNs) featuring stimuli-responsive behavior to diverse solute guests. The competitive coordination of metal ions to phenolic ligands of multiple coordination sites and solute guests (e.g., glucose) primarily determines the responsive behavior of the MPNs, as revealed experimentally and computationally. Glucose molecules can be embedded into the dynamic MPNs upon mixing, leading to the reconfiguration of the metal-organic networks and thus changes in their physicochemical properties for targeting applications. This study expands the library of stimuli-responsive flexible metal-organic materials and the understanding of intermolecular interactions between metal-organic materials and solute guests, which is essential for the rational design of responsive materials for various applications.

Admission Avoidance for Older Adults Facilitated by Telemedicine during the COVID-19 Pandemic.

INTRODUCTION: The coronavirus pandemic has disproportionately affected older adults and has provided an incentive to find alternatives to emergency department attendance to avoid unnecessary exposure to the SARS-CoV-2 virus. To address this issue, a specialist geriatric multidisciplinary team at Queen Elizabeth Hospital set up a novel telemedicine approach to the ambulance service with the aim of reducing unnecessary emergency department attendance for older adults. This study provides a service evaluation in its first year of use. METHODS: Service evaluation in the first year of the 'Ask OPAL' (older person Assessment and liaison) hotline for ambulance paramedics, run by a multidisciplinary acute geriatrics team at the Queen Elizabeth Hospital, Birmingham. Data on the number, patient demographics, intervention, and outcome of the calls, were recorded. RESULTS: During the study period, 2552 'Ask OPAL' calls were conducted. Of the 2552 calls carried out, 1755 patients (69%) remained at home. Of the patients who remained at home, 76% received verbal advice only, while 24% were referred to community services in addition to receiving verbal advice. CONCLUSION: In conclusion, the use of an integrated multidisciplinary team communicating with paramedics via telemedicine appears to be successful in preventing avoidable hospital admissions in complex patients.

Site-Selective Coordination Assembly of Dynamic Metal-Phenolic Networks.

Coordination states of metal-organic materials are known to dictate their physicochemical properties and applications in various fields. However, understanding and controlling coordination sites in metal-organic systems is challenging. Herein, we report the synthesis of site-selective coordinated metal-phenolic networks (MPNs) using flavonoids as coordination modulators. The site-selective coordination was systematically investigated experimentally and computationally using ligands with one, two, and multiple different coordination sites. Tuning the multimodal Fe coordination with catechol, carbonyl, and hydroxyl groups within the MPNs enabled the facile engineering of diverse physicochemical properties including size, selective permeability (20-2000 kDa), and pH-dependent degradability. This study expands our understanding of metal-phenolic chemistry and provides new routes for the rational design of structurally tailorable coordination-based materials.

Electromagnetic bioeffects: a multiscale molecular simulation perspective.

Electromagnetic bioeffects remain an enigma from both the experimental and theoretical perspectives despite the ubiquitous presence of related technologies in contemporary life. Multiscale computational modelling can provide valuable insights into biochemical systems and predict how they will be perturbed by external stimuli. At a microscopic level, it can be used to determine what (sub)molecular scale reactions various stimuli might induce; at a macroscopic level, it can be used to examine how these changes affect dynamic behaviour of essential molecules within the crowded biomolecular milieu in living tissues. In this review, we summarise and evaluate recent computational studies that examined the impact of externally applied electric and electromagnetic fields on biologically relevant molecular systems. First, we briefly outline the various methodological approaches that have been employed to study static and oscillating field effects across different time and length scales. The practical value of such modelling is then illustrated through representative case-studies that showcase the diverse effects of electric and electromagnetic field on the main physiological solvent - water, and the essential biomolecules - DNA, proteins, lipids, as well as some novel biomedically relevant nanomaterials. The implications and relevance of the theoretical multiscale modelling to practical applications in therapeutic medicine are also discussed. Finally, we summarise ongoing challenges and potential opportunities for theoretical modelling to advance the current understanding of electromagnetic bioeffects for their modulation and/or beneficial exploitation in biomedicine and industry.

Thoracic VGluT2+ Spinal Interneurons Regulate Structural and Functional Plasticity of Sympathetic Networks after High-Level Spinal Cord Injury.

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide "dysautonomia." We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGluT2+ spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal-splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI. To test whether the onset and progression of SCI-induced sympathetic plasticity is neuron activity dependent, we selectively inhibited (or excited) thoracic VGluT2+ interneurons using chemogenetics. New data show that silencing VGluT2+ interneurons in female and male mice with a T3 SCI, using hM4Di designer receptors exclusively activated by designer drugs (Gi DREADDs), blocks structural plasticity and the development of dysautonomia. Specifically, silencing VGluT2+ interneurons prevents the structural remodeling of spinal sympathetic networks that project to lymphoid and endocrine organs, reduces the frequency of spontaneous autonomic dysreflexia (AD), and reduces the severity of experimentally induced AD. Features of SCI-induced structural plasticity can be recapitulated in the intact spinal cord by activating excitatory hM3Dq-DREADDs in VGluT2+ interneurons. Collectively, these data implicate VGluT2+ excitatory SpINs in the onset and propagation of SCI-induced structural plasticity and dysautonomia, and reveal the potential for neuromodulation to block or reduce dysautonomia after severe high-level SCI.SIGNIFICANCE STATEMENT In response to stress or dangerous stimuli, autonomic spinal neurons coordinate a "fight or flight" response marked by increased cardiac output and release of stress hormones. After a spinal cord injury (SCI), normally harmless stimuli like bladder filling can result in a "false" fight or flight response, causing pathological changes throughout the body. We show that progressive hypertension and immune suppression develop after SCI because thoracic excitatory VGluT2+ spinal interneurons (SpINs) provoke structural remodeling in autonomic networks within below-lesion spinal levels. These pathological changes can be prevented in SCI mice or phenocopied in uninjured mice using chemogenetics to selectively manipulate activity in VGluT2+ SpINs. Targeted neuromodulation of SpINs could prevent structural plasticity and subsequent autonomic dysfunction in people with SCI.

Origins of Structural Elasticity in Metal-Phenolic Networks Probed by Super-Resolution Microscopy and Multiscale Simulations.

Metal-phenolic networks (MPNs) are amorphous materials that can be used to engineer functional films and particles. A fundamental understanding of the heat-driven structural reorganization of MPNs can offer opportunities to rationally tune their properties (e.g., size, permeability, wettability, hydrophobicity) for applications such as drug delivery, sensing, and tissue engineering. Herein, we use a combination of single-molecule localization microscopy, theoretical electronic structure calculations, and all-atom molecular dynamics simulations to demonstrate that MPN plasticity is governed by both the inherent flexibility of the metal (FeIII)-phenolic coordination center and the conformational elasticity of the phenolic building blocks (tannic acid, TA) that make up the metal-organic coordination complex. Thermal treatment (heating to 150 °C) of the flexible TA/FeIII networks induces a considerable increase in the number of aromatic π-π interactions formed among TA moieties and leads to the formation of hydrophobic domains. In the case of MPN capsules, 15 min of heating induces structural rearrangements that cause the capsules to shrink (from ∼4 to ∼3 µm), resulting in a thicker (3-fold), less porous, and higher protein (e.g., bovine serum albumin) affinity MPN shell. In contrast, when a simple polyphenol such as gallic acid is complexed with FeIII to form MPNs, rigid materials that are insensitive to temperature changes are obtained, and negligible structural rearrangement is observed upon heating. These findings are expected to facilitate the rational engineering of versatile TA-based MPN materials with tunable physiochemical properties for diverse applications.

Predicting wavelength-dependent photochemical reactivity and selectivity.

Predicting the conversion and selectivity of a photochemical experiment is a conceptually different challenge compared to thermally induced reactivity. Photochemical transformations do not currently have the same level of generalized analytical treatment due to the nature of light interaction with a photoreactive substrate. Herein, we bridge this critical gap by introducing a framework for the quantitative prediction of the time-dependent progress of photoreactions via common LEDs. A wavelength and concentration dependent reaction quantum yield map of a model photoligation, i.e., the reaction of thioether o-methylbenzaldehydes via o-quinodimethanes with N-ethylmaleimide, is initially determined with a tunable laser system. Combined with experimental parameters, the data are employed to predict LED-light induced conversion through a wavelength-resolved numerical simulation. The model is validated with experiments at varied wavelengths. Importantly, a second algorithm allows the assessment of competing photoreactions and enables the facile design of λ-orthogonal ligation systems based on substituted o-methylbenzaldehydes.

Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury.

After spinal cord injury (SCI), normally innocuous visceral or somatic stimuli can trigger uncontrolled reflex activation of sympathetic circuitry, causing pathological dysautonomia. We show that remarkable structural remodeling and plasticity occur within spinal autonomic circuitry, creating abnormal sympathetic reflexes that promote dysautonomia. However, when mice are treated early after SCI with human-equivalent doses of the US Food and Drug Administration (FDA)-approved drug gabapentin (GBP), it is possible to block multi-segmental excitatory synaptogenesis and abolish sprouting of autonomic neurons that innervate immune organs and sensory afferents that trigger pain and autonomic dysreflexia (AD). This "prophylactic GBP" regimen decreases the frequency and severity of AD and protects against SCI-induced immune suppression. These benefits persist even 1 month after stopping treatment. GBP could be repurposed to prevent dysautonomia in at-risk individuals with high-level SCI.

Electrostatic Activation of Tetrazoles.

Photoactivation of tetrazoles to form nitrile imines primed for 1,3-dipolar cycloaddition reactions is of widespread utility in chemistry. In contrast, the corresponding thermal reactions usually possess prohibitively high barriers and have garnered significantly less attention. Here, computational chemistry at the M06-2X/6-31+G(d,p) level of theory with SMD solvent corrections is used to show that these thermal activation barriers can be significantly reduced through the use of nonconjugated charged functional groups (CFGs). For 2,5-dimethyl-tetrazole, a positive CFG on the N-methyl (2-position) lowers the fragmentation barrier by around 80 kJ mol-1 in the gas phase, while a negative charge has a smaller opposite effect. These CFG effects remain significant even in polar solvents, with barrier lowering on the order of 30 kJ mol-1 in dimethyl sulfoxide and acetonitrile. In practical terms, the positive CFG decreases the fragmentation half-life of 2,5-dimethyl-tetrazole in refluxing o-xylene from 300,000 years to 1 week. While the resulting nitrile imine is stabilized, its subsequent 1,3-cycloaddition with N-methylmaleimide remains highly facile. Electrostatic effects on a range of 2-phenyl-5-methyltetrazoles, 2-methyl-5-phenyl-tetrazoles, and 2,5-diphenyl-tetrazoles follow similar trends and are explicable largely in terms of the stabilization of the developing dipole in the transition state.

Computational Optimization of Alkoxyamine-based Electrochemical Methylation.

Computational chemistry at the G3(MP2)-RAD//M06-2X/6-31+G(d,p)//SMD level of theory was used to study the oxidation of a test set of methyl adducts of nitroxide radicals and methyl adducts of Blatter's radical, a Kuhn verdazyl and two oxo-verdazyls. The barriers and the reaction energies of the SN2 reactions of the oxidized species with pyridine were also studied with a view to identify species with both low oxidation potentials and low SN2 barriers, so as to broaden the functional group tolerance of in situ electrochemical methylation compared with TEMPO-Me (1-methoxy-2,2,6,6-tetramethylpiperidine). Within the alkoxyamines, the oxidation potentials covered a range of 0.5 V, with trends explicable in terms of electrostatics, ring strain, and charge transfer. The oxidation potentials of oxo-verdazyl adducts, verdazyl adducts, and particularly the methyl adducts of Blatter's radical were considerably low due to the ability of their extensive π-systems to stabilize a positive charge. As expected, the SN2 reaction energies of the oxidized substrate became less favorable as the oxidation potential decreases. Unfortunately, this also meant that the barriers increased due to the excellent Evans-Polanyi correlation (R2 = 0.92). Nonetheless, 7-methoxy-7-azadispiro[5.1.5.836]hexadecane, N,N-di-tert-butyl-O-methylhydroxylamine, and particularly 1-methoxy-2,2,5,5-tetramethylpyrrolidine were identified as suitable candidates for broadening the scope of in situ electrochemical methylation while maintaining comparable kinetics to known reagents.

Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter.

Respiring mitochondria establish a proton gradient across the mitochondrial inner membrane (MIM) that is used to generate ATP. Protein-independent mitochondrial uncouplers collapse the proton gradient and disrupt ATP production by shuttling protons back across the MIM in a protonophoric cycle. Continued cycling relies on the formation of MIM-permeable anionic species that can return to the intermembrane space after deprotonation in the mitochondrial matrix. Previously described protonophores contain acidic groups that are part of delocalised π-systems that provide large surfaces for charge delocalisation and facilitate anion permeation across the MIM. Here we present a new class of protonophoric uncoupler based on aryl-urea substituted fatty acids in which an acidic group and a π-system are separated by a long alkyl chain. The aryl-urea group in these molecules acts as a synthetic anion receptor that forms intermolecular hydrogen bonds with the fatty acid carboxylate after deprotonation. Dispersal of the negative charge across the aryl-urea system produces lipophilic dimeric complexes that can permeate the MIM and facilitate repeated cycling. Substitution of the aryl-urea group with lipophilic electron withdrawing groups is critical to complex lipophilicity and uncoupling activity. The aryl-urea substituted fatty acids represent the first biological example of mitochondrial uncoupling mediated by the interaction of a fatty acid and an anion receptor moiety, via self-assembly.

Oriented Internal Electrostatic Fields Cooperatively Promote Ground- and Excited-State Reactivity: A Case Study in Photochemical CO2 Capture.

Oriented electrostatic fields can exert catalytic effects upon both the kinetics and the thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground-state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc. 2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground- and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvents, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.

Mechanistic Insights into N-Acyloxyamine-Initiated Controlled Degradation of Polypropylene: The Unexpected Role of Keto-Enol Tautomerization in Carboxylate Radical Chemistry.

Controlled degradation of polypropylene (PP) is used industrially to improve the properties of crude PP. While this degradation is traditionally initiated by organic peroxides, N-acyloxyamines are now preferred due to their greater stability. However, their mechanism of action remains unclear. Using high-level ab initio calculations, we show that N-O homolysis is the most likely fragmentation pathway available to N-acyloxyamines, in contrast to the more usual C-O homolysis observed for the closely related N-alkoxyamines. This would, in theory, generate aminyl and carboxylate radicals, with the latter undergoing decarboxylation to generate methyl radicals. However, the enol forms of N-acyloxyamines are significantly less thermally stable, having bond dissociation free energies that are over 50 kJ/mol below those of their keto equivalents. Under conditions where keto-enol tautomerism is feasible, enol N-O homolysis, which forms the more stable acetic acid radical, would be the dominant degradation pathway. This reveals the crucial and underappreciated role that polar impurities play in the initiation process of enolizable initiators and may explain contradictory observations in the experimental literature. The product aminyl radicals are susceptible to ß-fragmentation, releasing alkyl radicals and affording imines, which in turn are susceptible to allylic H-abstraction and further ß-fragmentation leading to dialkylpyridines as the ultimate degradation products.

Rational Design of Highly Activating Ligands for Cu-Based Atom Transfer Radical Polymerization.

Atom transfer radical polymerization (ATRP) is the most commonly utilized technique in controlled radical polymerization. However, the identification of more active catalysts could further increase its scope, both for polymerization and small-molecule synthesis more generally. To this end, a series of novel ligands were designed on the basis of two strategies: replacing nitrogen-based ligands with their phosphorus equivalents and rigidifying the ligand cap of nitrogen-based ligands so as to enforce short Cu-cap distances. Each ligand was assessed using accurate computational chemistry, which was used to compute the thermodynamics and, in selected cases, kinetics of an ATRP reaction with a model methyl methacrylate propagating radical. In principle, the use of phosphorus ligand caps was found to be a powerful strategy for increasing catalyst activity. Unfortunately, in practice, speciation issues sacrificed much of their advantage. In contrast, cap rigidification increases the activity of nitrogen-based ligands, well beyond existing ATRP ligands such as TPMANMe2. The effectiveness of these ligands was further demonstrated for hard-to-activate initiating systems based on ethylene, vinyl chloride, and vinyl acetate polymerization. Several of these improved ligands are synthetically accessible, with rigid piperidine or quinuclidine analogues of TPMANMe2 possessing improved thermodynamic and kinetic activity by 2 to 3 orders of magnitude.

TEMPO-Me: An Electrochemically Activated Methylating Agent.

Bench- and air-stable 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO-Me) is relatively unreactive at ambient temperature in the absence of an electrochemical stimulus. In this report, we demonstrate that the one-electron electrochemical oxidation of TEMPO-Me produces a powerful electrophilic methylating agent in situ. Our computational and experimental studies are consistent with methylation proceeding via a SN2 mechanism, with a strength comparable to the trimethyloxonium cation. A protocol is developed for the electrochemical methylation of aromatic acids using TEMPO-Me.

Discrete and Stereospecific Oligomers Prepared by Sequential and Alternating Single Unit Monomer Insertion.

Natural biopolymers, such as DNA and proteins, have uniform microstructures with defined molecular weight, precise monomer sequence, and stereoregularity along the polymer main chain that affords them unique biological functions. To reproduce such structurally perfect polymers and understand the mechanism of specific functions through chemical approaches, researchers have proposed using synthetic polymers as an alternative due to their broad chemical diversity and relatively simple manipulation. Herein, we report a new methodology to prepare sequence-controlled and stereospecific oligomers using alternating radical chain growth and sequential photoinduced RAFT single unit monomer insertion (photo-RAFT SUMI). Two families of cyclic monomers, the indenes and the N-substituted maleimides, can be alternatively inserted into RAFT agents, one unit at a time, allowing the monomer sequence to be controlled through sequential and alternating monomer addition. Importantly, the stereochemistry of cyclic monomer insertion into the RAFT agents is found to be trans-selective along the main chains due to steric hindrance from the repeating monomer units. All investigated cyclic monomers provide such trans-selectivity, but analogous acyclic monomers give a mixed cis- and trans-insertion.

The spleen as a neuroimmune interface after spinal cord injury.

Traumatic spinal cord injury (SCI) causes widespread damage to neurons, glia and endothelia located throughout the spinal parenchyma. In response to the injury, resident and blood-derived leukocytes orchestrate an intraspinal inflammatory response that propagates secondary neuropathology and also promotes tissue repair. SCI also negatively affects autonomic control over peripheral immune organs, notably the spleen. The spleen is the largest secondary lymphoid organ in mammals, with major roles in blood filtration and host defense. Splenic function is carefully regulated by neuroendocrine mechanisms that ensure that the immune responses to infection or injury are proportionate to the initiating stimulus, and can be terminated when the stimulus is cleared. After SCI, control over the viscera, including endocrine and lymphoid tissues is lost due to damage to spinal autonomic (sympathetic) circuitry. This review begins by examining the normal structure and function of the spleen including patterns of innervation and the role played by the nervous system in regulating spleen function. We then describe how after SCI, loss of proper neural control over splenic function leads to systems-wide neuropathology, immune suppression and autoimmunity. We conclude by discussing opportunities for targeting the spleen to restore immune homeostasis, reduce morbidity and mortality, and improve functional recovery after SCI.

Effect of heteroatom and functionality substitution on the oxidation potential of cyclic nitroxide radicals: role of electrostatics in electrochemistry.

The oxidation potential of a test set of 21 nitroxide radicals, including a number of novel compounds, has been studied experimentally in acetonitrile and correlated with theoretical calculations. It was found that both Hammett constants (σp) of the substituents on the nitroxide radicals and hyperfine splitting constants of the respective nitrogen atoms (αN) were well correlated to their experimental oxidation potentials. Theoretical calculations, carried out at the G3(MP2,CC)(+)//M06-2X/6-31+G(d,p) level of theory with PCM solvation corrections, were shown to reproduce experiments to within a mean absolute deviation of 33 mV, with a maximum deviation of 64 mV. The oxidation potentials of the nitroxides examined varied over 400 mV, depending on ring size and substitution. This considerable variation can be rationalised by the ability of various substituents to electrostatically stabilize the oxidised oxoammonium cation. Importantly, this can be quantified by a simple predictive relationship involving the distance scaled dipole and quadrupole moments of the analogous cyclohexyl ring. This highlights the often-overlooked role of through-space electrostatic substituent effects, even in formally neutral compounds.