Enthalpic and entropic contributions to the basicity of cycloalkylamines

Perrin, Charles L.; Shrinidhi, Annadka

doi:10.1039/d0sc02931a

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…Organic bases often show a solvent dependency in their basicity, 46 and factors such as steric hindrance and the enthalpic and entropic contributions associated with the protonation of cyclic amines may exert an additional influence. 47 Moreover, the nucleophilicity of secondary amines is also solvent dependent, 48,49 and an increased basicity and/or nucleophilicity for pyrrolidine compared to piperidine could impact side-product formation. To this end, we first investigated the efficiency of pyrrolidine removal from the resin by washing with selected binary solvent mixtures and then assessed the extent of the base-dependent side-reactions aspartimide and diketopiperazine (DKP) formation when using pyrrolidine as the base for Fmoc-removal.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…However, as we have demonstrated, pyrrolidine is a more accomplished base than piperidine for Fmoc-removal in less polar solvent mixtures. Organic bases often show a solvent dependency in their basicity, and factors such as steric hindrance and the enthalpic and entropic contributions associated with the protonation of cyclic amines may exert an additional influence . Moreover, the nucleophilicity of secondary amines is also solvent dependent, , and an increased basicity and/or nucleophilicity for pyrrolidine compared to piperidine could impact side-product formation.…”

Section: Resultsmentioning

confidence: 99%

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Fmoc-Removal with Pyrrolidine Expands the Available Solvent Space in Green Solid-Phase Peptide Synthesis

Egelund

Jadhav

Martin

et al. 2021

ACS Sustainable Chem. Eng.

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Green binary solvent mixtures with a polarity and viscosity close to that of DMF perform similarly in solid-phase peptide synthesis (SPPS). However, while coupling reactions readily proceed in solvents of significantly lower polarity than that of DMF, a high solvent polarity is essential for Fmoc-removal using piperidine, which limits the options for green SPPS solvents. Herein, we report our efforts to expand the available solvent polarity space for green SPPS. We identified pyrrolidine as an efficient base to enable Fmoc-removal in less polar solvent mixtures that also favor coupling reactions, such as dimethyl sulfoxide/ethyl acetate (1:9) and N-butylpyrrolidone/1,3-dioxolane (2:8 and 4:6). Employing less polar binary solvent mixtures in combination with pyrrolidine gave crude peptide purities comparable to or better than for DMF with piperidine in the SPPS of challenging peptide targets. An evaluation of base-dependent side reactions such as diketopiperazine (DKP) and aspartimide formation showed increased side-product formation when using pyrrolidine on DKP- and aspartimide-prone sequences. However, the scaled-up syntheses (5 and 7.5 mmol, respectively) of the peptide therapeutics dasiglucagon (29-mer) and bivalirudin (20-mer) gave good crude peptide purities and purity profiles amenable to SPPS optimization. Pyrrolidine therefore represents a useful alternative to piperidine for Fmoc-removal in an expanded solvent space for green SPPS.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fmoc-Removal with Pyrrolidine Expands the Available Solvent Space in Green Solid-Phase Peptide Synthesis

Egelund

Jadhav

Martin

et al. 2021

ACS Sustainable Chem. Eng.

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“…ΔS ‡ significantly decreased from −41.0 ± 8.8 to −80.3 ± 6.6 J K −1 mol −1 after the introduction of CB [7], which had a major contribution on the deceleration of the reaction. One plausible reason is that the reorganization of solvent is influenced by the steric hindrance effect of CB [7], 49 thus leading to a more negative ΔS ‡ . In addition, the second-order rate constant k b was decreased after the introduction of CB [7] (see Figure S6), indicating that the H/D exchange of APTA became less sensitive to the concentration change of OD − .…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Cucurbit[7]uril-Modulated H/D Exchange of α-Carbonyl Hydrogen: Deceleration in Alkali and Acceleration in Acid Conditions

Jiao

Tang

et al. 2021

Langmuir

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Supramolecular catalysis based on host−guest interactions has aroused much attention in past decades. Among the various strategies, modulation of the reactivity of key intermediates is an effective strategy to achieve high-efficiency supramolecular catalysis. Here, we report that by utilizing the host− guest interaction of cucurbit[7]uril (CB[7]), the reactivity of anionic enolate and cationic oxonium, the intermediates of H/D exchange of the α-carbonyl hydrogen in alkali and acid conditions, respectively, could be modulated effectively. On one hand, in alkaline conditions, both the electrostatic effect and the steric hindrance effect of CB [7] disfavored formation of the enolate anion intermediate. On the other hand, in acidic conditions, the oxonium was stabilized and the solvent effect was weakened by the electrostatic effect of CB [7]. As a result, the H/D exchange of 1-(4-acetylphenyl)-N,N,N-trimethylmethanaminium bromide is decelerated in alkaline and accelerated in acidic conditions. It is promising that the highly polar portals of CB[n] molecules together with their well-defined host−guest chemistry may be applied to modulate the reactivity of other kinds of ionic intermediates in an effective and convenient way, thus enriching the toolkit of supramolecular catalysis.

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“…Taking a different administration route, scientists devised nanofiber patches for the transdermal delivery of curcumin. The transdermal route has gained recognition as an alternative to conventional oral delivery for various drugs, with numerous studies indicating improved bioavailability via this route [64][65][66][67][68][69][70][71][72][73]. These nanofibers were created using polyvinyl alcohol and gelation, resulting in a formulation characterized by fiber diameters of 200-250 nm and high reproducibility [74][75][76][77][78].…”

Section: Drug Delivery Approaches For Bioactive Compounds In the Trea...mentioning

confidence: 99%

Advancements in Drug Delivery Systems for Natural Compounds Targeting Metabolic Disorders Associated with Inflammation

Sam,

Neal

2023

Arch Gastroenterol Res

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The global incidence of metabolic disorders is on the rise, posing a significant challenge to public health. With remarkable advancements in diagnostic tools and clinical procedures, our understanding of the etiology and underlying pathophysiology of these disorders has expanded considerably. Furthermore, the utilization of in vitro and in vivo experimental models, preceding clinical investigations, has catalyzed numerous breakthroughs in biomedicine, particularly in the identification and development of potential drug candidates for the management of metabolic disorders. Natural compounds isolated from various sources have garnered extensive attention as prospective drug candidates for the treatment of conditions such as diabetes, obesity, heart-related diseases, and cancer. This interest is partly attributed to their inherent antioxidant and anti-inflammatory properties. Concurrently, intensive research efforts have been directed towards enhancing the bioactivity and bioavailability of these compounds through selected drug delivery strategies. In this article, we provide valuable insights into recent advancements that shed light on the role of inflammatory-mediated responses in the initiation of metabolic disorders, with a specific focus on conditions like diabetes mellitus, obesity, heart-related diseases, cancer, and related drug delivery systems. Additionally, we explore the promising potential of natural products in managing these metabolic disorders. Furthermore, we present lists of potential biological targets suitable for high throughput screening in the drug discovery and development process. Finally, we delve into the findings gleaned from preclinical and clinical studies, setting the stage for the identification of suitable approaches in the realm of phytochemical drug delivery systems that hold promise for the treatment of metabolic disorders.

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Enthalpic and entropic contributions to the basicity of cycloalkylamines

Abstract: Large-ring cycloalkylamines are slightly less basic than other cycloalkylamines such as cyclohexylamine, even though all have tetrahedral carbons and are strain-free.

Cited by 6 publications

References 39 publications

Fmoc-Removal with Pyrrolidine Expands the Available Solvent Space in Green Solid-Phase Peptide Synthesis

Fmoc-Removal with Pyrrolidine Expands the Available Solvent Space in Green Solid-Phase Peptide Synthesis

Cucurbit[7]uril-Modulated H/D Exchange of α-Carbonyl Hydrogen: Deceleration in Alkali and Acceleration in Acid Conditions

Advancements in Drug Delivery Systems for Natural Compounds Targeting Metabolic Disorders Associated with Inflammation

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