Influence of solvent mixture on nucleophilicity parameters: the case of pyrrolidine in methanol–acetonitrile

Souissi, Salma; Gabsi, Wahiba; Echaieb, Abderraouf; Roger, Julien; Hierso, Jean‐Cyrille; Fleurat‐Lessard, Paul; Boubaker, Taoufik

doi:10.1039/d0ra06324j

Cited by 15 publications

(17 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. 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: 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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…As discussed in previous studies of the S N Ar reactions, 31–36 the application of the steady‐state approximation with respect to zwitterionic intermediate T ± to Scheme 1 gives the following relationship. On the other hand, if the rate‐determining step is the formation of zwitterionic intermediate T ± (i.e., k −1 < < ( k 2 + k 3 [aniline])), Equation (2) simplifies to Equation (3):

k_{obsd} = \frac{k_{1} false(k_{2} + k_{3} [aniline] false)}{k_{- 1} + k_{2} + k_{3} false[aniline false]} false[aniline false],

k_{obsd} = k_{1} [aniline] .

…”

Section: Resultsmentioning

confidence: 86%

Nucleophilicities of para‐substituted aniline radical cations in acetonitrile: Kinetic investigation and structure–reactivity relationships

Amira

Souissi

Gabsi

et al. 2021

Int J of Chemical Kinetics

View full text Add to dashboard Cite

The kinetics of the coupling of 2‐bromo‐3,5‐dinitrothiophene 1 with various anilines 2a–f were studied in CH3CN at 20°C. The derived second‐order rate constants of anilines possessing an electron‐withdrawing group (e.g., 2d–f) were employed to determine the electrophilicity parameter E of the thiophene 1 according to the correlation equation log k20°C = sN (E + N), where N and sN are nucleophile‐specific parameters. Nonlinear Brønsted and Hammett relationships are discussed, and it is shown that the reactions for donor anilines 2a–d proceed through a single‐electron transfer mechanism. Further support for this assumption was given by the observation that the nucleophilicity parameters N and E° values of oxidation potential constants are linearly related in a direct relationship with a correlation parameter of R2 = 0.9914. The effect of aniline nucleophilicity on reactivity was examined quantitatively on the basis of kinetic measurements, leading to a nonlinear relationship of log (k20°C) with nucleophilicity parameters (N). It is suggested that the observed nonlinear Mayr correlation can be effectively explored to evaluate the nucleophilicity parameters N of four‐substituted aniline radical cations XC6H4NH2+• (X = OH, OMe, Me) and studying their reactivity patterns. On the other hand, it is confirmed that the N values of HOC6H4NH2+• (15.60), MeOC6H4NH2+• (15.23) and MeC6H4NH2+• (14.19) thus obtained can be used to predict the second‐order rate constants for their reactions with N1‐methyl‐4‐nitro‐2,1,3 benzothiadiazolium tetrafluoroborate of known electrophilicity E. This study was one of the first that employed the Mayr approach for determining nucleophilicity parameters of radical cations.

show abstract

“…In a recent study, we showed that the second-order rate constants for the reactions of 7-X-4-nitrobenzofurazans 1 (1a, X = Cl, 1b,X=OC 6 H 5 and 1c: X = OCH 3 ) with secondary cyclic amines 2 (2a, morpholine, 2b, piperidine and 2c, pyrrolidine) in acetonitrile at 20°C [27,29] can be described by the linear free energy relationship log k = s N (N+ E), [45][46][47][48] and we determined the E parameters of these electrophiles 1a-c which are collected in Figure 12. We have now used these parameters E in order to elucidate the relationship between Mayr's electrophilicities E [45] and Parr's global electrophilicity index w values [49,50].…”

Section: Correlation Analysismentioning

confidence: 99%

Structure-Property Relationships in Benzofurazan Derivatives: A Combined Experimental and DFT/TD-DFT Investigation

Raissi¹,

Chérif²,

Ayachi³

et al. 2022

Density Functional Theory - Recent Advances, New Perspectives and Applications

Self Cite

View full text Add to dashboard Cite

In this work we seek to understand and to quantify the reactivity of benzofurazan derivatives toward secondary cyclic amines, like pyrrolidine, piperidine and morpholine, acting as nucleophile groups in SNAr reactions. For this aim, physico-chemical and structural descriptors were determined experimentally and theoretically using the DFT/B3LYP/6-31+ g (d,p) methodology. Thus, different 4-X-7-nitrobenzofurazans (X = OCH3, OC6H5 and Cl) and products corresponding to the electrophilic aromatic substitution by pyrrolidine, piperidine and morpholine, were investigated. Particularly, the HOMO and LUMO energy levels of the studied compounds, determined by Cyclic Voltammetry (CV) and DFT calculations, were used to evaluate the electrophilicity index (ω). The latter was exploited, according to Parr’s approach, to develop a relationship which rationalizes the kinetic data previously reported for the reactions of the 4-X-7-nitrobenzofurazans with nucleophiles cited above. Moreover, the Parr’s electrophilicity index (ω) of these benzofurazans determined in this work were combined with their electrophilicity parameters (E), reported in preceding papers, was found to predict the unknown electrophilicity parameters E of 4-piperidino, 4-morpholino and 4-pyrrolidino-7-nitrobenzofurazan. In addition, the relationship between the Parr’s electrophilicity index (ω) and Hammett constants σ, has been used as a good model to predict the electronic effect of the nucleophile groups. Finally, we will subsequently compare the electrophilicity index (ω) and the electrophilicity parameters (E) of these series of 7-X-4-nitrobenzofurazans with the calculated dipole moment (μ) in order to elucidate general relationships between E, ω and μ.

show abstract

Influence of solvent mixture on nucleophilicity parameters: the case of pyrrolidine in methanol–acetonitrile

Abstract: Combined experiments and modelling rationalize the large influence of solvent composition on pyrrolidine nucleophilicity.

Cited by 15 publications

References 48 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

Nucleophilicities of para‐substituted aniline radical cations in acetonitrile: Kinetic investigation and structure–reactivity relationships

Structure-Property Relationships in Benzofurazan Derivatives: A Combined Experimental and DFT/TD-DFT Investigation

Contact Info

Product

Resources

About