Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in ...solvent-free - or highly solvent-minimised - reaction systems. Nevertheless, despite elegant advances in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports into the translation from "batch-mode" ball-milling to "flow-mode" reactive extrusion, using twin-screw extrusion.
Reactive extrusion provides a scale-up opportunity to turn a mechanochemical process from a ball-mill into continuous flow. This tutorial review summarises some of the early ground-breaking work in this area.
The use of temperature‐controlled mechanochemistry to enable the mechanochemical nickel‐catalyzed Suzuki–Miyaura coupling is herein described. Transitioning from a capricious room‐temperature ...protocol, through to a heated, PID‐controlled programmable jar heater manifold was required to deliver an efficient method for the coupling of aryl sulfamates (derived from ubiquitous phenols) and aryl boronic acid species. Furthermore, this process is conducted using a base‐metal nickel catalyst, in the absence of bulk solvent, and in the absence of air/moisture sensitive reaction set‐ups. This methodology is showcased through translation to large‐scale twin‐screw extrusion methodology enabling 200‐fold scale increase, producing decagram quantities of C−C coupled material.
The nickel catalyzed Suzuki–Miyaura‐type coupling of aryl sulfamates and boronic acid derivatives enabled by temperature‐controlled mechanochemistry via the development of a programmable PID‐controlled jar heater is reported. This base‐metal‐catalyzed, solvent‐free, all‐under‐air protocol was also scaled 200‐fold using twin‐screw extrusion technology affording decagram quantities of material.
Efforts to generate organomanganese reagents under ball‐milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. ...The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy, and solution control reactions. This unique reactivity can also be translated to solution whereupon pre‐milling of the manganese is required.
A manganese‐mediated reductive dimerization of arylidene malonates by ball milling is reported. The process has been optimised and its mechanism explored by CV measurements, radical trapping, and EPR spectroscopy. Control experiments identify the action of ball milling rather than mortar and pestle is necessary to realise the effective activation of manganese, which can then be used in either solution or a ball mill for subsequent reactions.
A base-mediated α-C-alkylation of ketones with secondary alcohols has been developed. This transition metal free approach employs KOt-Bu as the base and exhibits a broad scope, allowing a range of ...commodity aliphatic secondary alcohols and 1-arylethanols to be employed as alkylating agents. Aryl methyl ketones undergo selective mono-α-C-alkylation in high isolated yields (23 examples, 65% average yield).
Accurately measuring the ability of the K/HDEL receptor (ERD2) to retain the ER cargo Amy-HDEL has questioned earlier results on which the popular receptor recycling model is based upon. Here we ...demonstrate that ERD2 Golgi-retention, rather than fast ER export supports its function. Ligand-induced ERD2 redistribution is only observed when the C-terminus is masked or mutated, compromising the signal that prevents Golgi-to-ER transport of the receptor. Forcing COPI mediated retrograde transport destroys receptor function, but introducing ER-to-Golgi export or cis-Golgi retention signals re-activate ERD2 when its endogenous Golgi-retention signal is masked or deleted. We propose that ERD2 remains fixed as a Golgi gatekeeper, capturing K/HDEL proteins when they arrive and releasing them again into a subdomain for retrograde transport back to the ER. An in vivo ligand:receptor ratio far greater than 100 to 1 strongly supports this model, and the underlying mechanism appears to be extremely conserved across kingdoms.
The decline in C-peptide in the 5 years after diagnosis of type 1 diabetes has been well studied, but little is known about the longer-term trajectory. We aimed to examine the association between ...log-transformed C-peptide levels and the duration of diabetes up to 40 years after diagnosis.
We assessed the pattern of association between urinary C-peptide/creatinine ratio (UCPCR) and duration of diabetes in cross-sectional data from 1,549 individuals with type 1 diabetes using nonlinear regression approaches. Findings were replicated in longitudinal follow-up data for both UCPCR (
= 161 individuals, 326 observations) and plasma C-peptide (
= 93 individuals, 473 observations).
We identified two clear phases of C-peptide decline: an initial exponential fall over 7 years (47% decrease/year 95% CI -51, -43) followed by a stable period thereafter (+0.07%/year -1.3, +1.5). The two phases had similar durations and slopes in patients above and below the median age at diagnosis (10.8 years), although levels were lower in the younger patients irrespective of duration. Patterns were consistent in both longitudinal UCPCR (
= 162; ≤7 years duration: -48%/year -55, -38; >7 years duration -0.1% -4.1, +3.9) and plasma C-peptide (
= 93; >7 years duration only: -2.6% -6.7, +1.5).
These data support two clear phases of C-peptide decline: an initial exponential fall over a 7-year period, followed by a prolonged stabilization where C-peptide levels no longer decline. Understanding the pathophysiological and immunological differences between these two phases will give crucial insights into understanding β-cell survival.
Abstract Herein, we report on the translation of a small scale ball‐milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful ...translation were: a) understanding how the different operating parameters of a twin‐screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid‐liquid, solid–liquid and solid‐solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7‐hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).
Improving retention within randomised controlled trials is important. The effectiveness of different strategies can be assessed using a Study Within A Trial (SWAT). Previous research has shown ...personalised text message reminders improve clinic attendance rates; however, the results are mixed on improving postal questionnaire return. This SWAT aims to assess whether personalised text message reminders improve completion rates for scheduled telephone follow-ups.
This SWAT is a two-arm, multi-centre randomised controlled trial with equal allocation. The host trial was the Melatonin for Anxiety prior to General anaesthesia In Children trial (ISRCTN 18296119), where the child's caregiver was to answer a scheduled telephone follow-up 14 days post-surgery; participants for the SWAT were therefore the caregiver. Text messages were sent 24-48 h before the scheduled call and the personalised version contained the first name of the caregiver which was omitted in the non-personalised version. The primary outcome was questionnaire completion rate, defined as the proportion of caregivers successfully contacted, and completed any of the questionnaires, over the telephone within the follow-up window (day 14 + 7 days).
The SWAT included 100 of the 110 (91%) participants randomised into the host trial. Randomisation within the SWAT was equal between non-personalised (n = 50) and personalised (n = 50) interventions. The overall questionnaire response rate was 73% with a difference between the two interventions of 68% in the non-personalised text message arm and 78% in the personalised text message arm. The adjusted absolute risk difference was 7.1% (95% confidence interval = -10.2%, 24.4%). There was no difference in either the time to response or the number of contact attempts between the two interventions.
There is some evidence that personalised text messages could be effective at increasing response rates when data is collected via telephone and in a population of caregivers for paediatric trial participants. However, similar SWATs have shown mixed results. Given the low-cost and low risks associated with personalising text message reminders, this SWAT could be implemented easily in other RCTs scheduling telephone follow-up appointments.
ISRCTN 18296119 , SWAT 35 (MRC Northern Ireland Network for Trials Methodology Network).
Chitin‐derived furans offer a sustainable alternative feedstock for nitrogen appended aromatic compounds. Herein, we address the challenge of using chitin‐derived furans, 3‐acetamido‐5‐acetylfuran ...(3A5AF) and 3‐acetamido‐5‐furfural aldehyde (3A5F), to favour the formation of exo Diels–Alder adducts and 4‑acetylaminophthalimides respectively, using a mechanochemical ball‐milling technique. Mechanochemical activation is explored through the synthesis of 7‐oxa‐norbornene backbones with novel substitution pattern from 3A5AF in yields up to 77% and improved exo:endo selectivity compared to solution‐phase reactions. The synthesis of 4‑acetylaminophthalimides from 3A5F in yields up to 79% is also showcased from hydrazone derivatives.
Melatonin's effectiveness as an anxiolytic medication has been confirmed in adults; however, its efficacy in a paediatric population is unclear. A number of small studies have assessed its use in ...children as a pre-operative anxiolytic, with conflicting results.
We undertook a systematic review of pre-operative melatonin use in children. Four databases (MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science), and ' ClinicalTrials.gov ' were searched for ongoing and completed clinical trials of relevance. Citation tracking reference lists and relevant articles were also accessed. The review was unrestricted by comparator or outcomes. Eleven studies were judged eligible for inclusion. There were high levels of heterogeneity in melatonin administration (in terms of dose and timing). Variable outcomes were reported and included: anxiety; anaesthetic success; analgesia; sedation; post-operative recovery; and safety. Outcomes were not always assessed with the same measures.
Evidence to support melatonin's anxiolytic properties in this setting is conflicting. Melatonin was associated with reduced sedative effects, post-operative excitement and improved emergence behaviour, compared to comparator drugs. One study reported the benefit of melatonin use on sleep disturbance at two weeks post-surgery. No adverse safety events were identified to be significantly associated with melatonin, affirming its excellent safety profile.
Despite potential advantages, including improved emergence behaviour, based on current evidence we cannot confirm whether melatonin is non-inferior to current "usual care" pre-medications. Further consideration of melatonin as an anxiolytic pre-medication in paediatric surgery is needed.
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