Stepwise PEG synthesis featuring deprotection and coupling in one pot

• Logan Mikesell,
• Dhananjani N. A. M. Eriyagama,
• Yipeng Yin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2021, 17, 2976–2982, doi:10.3762/bjoc.17.207

• was observed after warming the reaction mixture to −50 °C and stirring at the temperature for less than two hours. Because LDA has a short shelf life, and has to be stored at low temperature, we were curious if KHMDS (pKa of conjugate acid, 26), which is a much weaker base than LDA (pKa of conjugate

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• ), as functional groups on the polymer chains can have weak acidic characteristics if they release protons, or weak basic characteristics if they accept protons, in response to changes in pH. This can come about from even small variations in solution pH, depending on the degree of ionisation and pKa

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• allylic functionalization of 2-alkylazaarenes. Due to the high pKa value of alkyl azaarenes, the functionalization of benzylic C(sp3)–H was challengeable and pre-activation of the benzylic proton with suitable Lewis acids was often required prior to deprotonation of the alkyl chain by a stoichiometric

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes

• Martin Kamlar,
• Robert Reiberger,
• Martin Nigríni,
• Ivana Císařová and
• Jan Veselý

Beilstein J. Org. Chem. 2021, 17, 2433–2440, doi:10.3762/bjoc.17.160

• derivatives. PCCPs were firstly reported by Otto Diels [28][29], but recently, Lambert and co-workers introduced a new generation, chiral PCCPs (Figure 1) [30]. Due to the high stability of the aromatic cyclopentadienyl anion, PCCPs exhibit a low pKa value comparable to that of phosphoric acids. Contrary to

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• -4j < unsubstituted 4a < 3,5-diCl 4t < 2,6-diCl 4r < pentachloro 4v, in good agreement with the decreasing order of the pKa values of the pyridines. For example, in order to fluorinate phenol, triMe 5-4j needed heating at 100 °C in a haloalkane solvent for 24 h, whereas pentachloro 5-4v required only

• these reagents exhibited a low reactivity due to their low solubility in organic solvents [32]. Their fluorinating power increased in the order of 18-2a < 2b ≈ 2c ≈ 2d ≈ 2e < 2f < 2g < 2h, consistent with the order of the pKa values of the pyridines (Scheme 39). The least powerful 18-2a was suitable for

• -fluoropyridinium triflate (Scheme 53), which is again in good agreement with the pKa values of the bipyridines. The 2,2’-isomers had the highest power (reactivity) among the dipyridinium isomers, and they were much more reactive than the monomeric N-fluoropyridinium triflate (5-4a). In contrast to the N,N

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• , in this case, the activity of the catalyst is not rate determining. This observation is rationalized by the occurrence of a non-productive acid–base equilibrium involving the de- and re-protonation of the considerably acidic alkyne proton in d (pKa = 15.61 [20]) [21]. The reaction conditions

• reaction conditions, i.e., reaction temperatures and times not exceeding 80 °C and 24 h) without the unconditional need to exclude oxygen. A first hint for rationalizing the different reactivity of the different phosphines can be retrieved from the pKa value of their conjugated acids. Substitution of the

• aromatic rings with methoxy groups increases the pKa value from 1.31 (TPP) to 4.20 (TMTPP) (Figure 1). Methyl cation affinities (MCA) which can be used as descriptors for the nucleophilicity of a compound were calculated by Lindner et al. who suggested TMTPP (651.0 kJ/mol) to be a stronger Lewis base than

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• -bonding (Figure 6) [94]. A significant bottleneck for triple helix formation is the requirement for cytosine protonation to form the natural C+•G–C triplet. Because of the low pKa of cytosine (≈4.5), formation of the C+•G–C triplet is unfavorable at physiological pH, which severely destabilizes the

• parallel triple helices and limits their applications in biological systems. Two obvious strategies to solve this problem are to modify the cytosine heterocycle to either 1) increase the pKa or 2) create neutral analogues of protonated cytosine. In the latter strategy, Ono et. al. introduced

• subtle modulation of the pKa and better π-stacking [99]. Several other research groups have further increased the pKa value by removing electronegative substituents from C arriving at derivatives of 2-aminopyridine (M, Figure 6) as more basic nucleobases that improve binding of triplex-forming

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• has a similar pKa to a carboxylate yet provides enhanced hydrogen bonding capability and alternative prospects for permeability due to a larger hydrophobic region enabling improved lipophilic contacts. These alternative properties and a prospect for their inclusion within new alginate fragments led us

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• showed traces of [2.2]metaparacyclophane (3). A quick investigation of the strengths of acids required to cause rearrangement revealed that both triflic acid (pKa = −14) and perchloric acid (pKa = −10) were sufficiently strong to cause rearrangement while nitric (−1.3), sulfuric (−3.0), and acetic acids

• (4.8) were all too weak. While these results seem to make sense, when we compare the pKa values, they do not explain why a mixture of nitric and sulfuric acids causes rearrangement. It is possible that we are comparing the wrong values. pKa measures acidity in water. Under our reaction conditions it

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• represented as the major tautomer 1b with the conjugated system –C=N–C=N– and the numbering of the different atoms will be established as depicted in Figure 1. Biguanides are relatively strong bases, with pKa1H ≈ 11.5 (pKa of the conjugate acid of biguanide); however, significantly less basic than guanidine

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• additive having a similar pKa value to that of H2SO3 that is likely to be present in liquid SO2 (Table 2, entries 3 and 8) [55]. Thus, the previously considered probable contributory effect of H2SO3 can be ruled out. Further, in combination with polar aprotic Lewis basic solvents (MeCN, THF) [67] sulfur

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• , like DMSO or DMF or in polar protic solvents like alcohols. For carbon acids the ΔpKa is 12.9 between ACN and DMSO but the ΔpKa is only −1.5 between DMF and DMSO [34]. A change of the solvent from acetonitrile to DMF should therefore decrease the pKa by ca. 11 units. In polar protic solvents (e.g., in

• substituent (4-OCH3; entry 2 in Table 3) enhances the yield to 88%. From these observations it is clear that the influence of R4 is much stronger than the influence of the substituent R1 (cf. entries 1 and 10–13 or entries 6 and 14–17 in Table 3). The attached EWG substituent R4 lowers the pKa (and thus also

• . This result is in accordance with the relatively low nucleofugality of diethyl phosphate which is roughly quantified by the pKa = 1.39 of its conjugated acid [43]. We have also examined an addition of 20% of tetrabutylammonium bromide as a nucleophilic catalyst which could transform the phosphate 1g in

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• deprotonated acetylacetone and diphenylmethane. Even there are reports on SNAr reactions of acetylacetone with purines and pyrimidines [56][80], in our hands only polymerization of acetylacetone was observed. On the other hand, the diphenylmethane anion (pKa 32; DMSO [81]) apparently is too basic and

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• amount of the moderately acidic (S)-TRIP (pKa = 3–4 in DMSO [113][114]) in dichloromethane afforded the chiral α-(trifluoromethyl)aminoaryl derivatives 177 in an excellent yield and enantiomeric excess (Scheme 42). The authors proposed that hemiacetal 175 and amine 176 react under the reaction conditions

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• stability over a wide pH value range (up to pH 9.0), irrespective of the temperature. This is because in compound 12, the ferulate moiety is not directly linked to the good leaving group 4NTC (pKa = 6.61 [40]). Instead, it is bonded to the linker with a pKa value that can be compared either to that of

• glycerol (pKa = 13.61) or ʟ-arabinose (pKa = 11.31) [41], meaning that it is a poor leaving group. Moreover, our observations regarding the linker stability are consistent with the known stability of the ester linkages under basic conditions. The usefulness of 4NTC–linker–Fe (12) for the characterization

Multiswitchable photoacid–hydroxyflavylium–polyelectrolyte nano-assemblies

• Alexander Zika and
• Franziska Gröhn

Beilstein J. Org. Chem. 2021, 17, 166–185, doi:10.3762/bjoc.17.17

• poly(allylamine) at pH 7.0. At this pH value, both the polyelectrolyte and also the photoacid are protonated [81][82]. Upon irradiation, the pKa of the photoacid decreases to pKa = −2.6 leading to deprotonation [82]. In addition to the electrostatic self-assembly of the photoacid and the

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• –Cl amide product 14. Closer inspection of the reaction progression by UV-LC–MS revealed the expected product 14 is formed first and is slowly transformed to 15 overnight. We postulated that the acidic HOAt (pKa = 3.76) liberated from the coupling reaction must be protonating thus activating the basic

• obtained for the 3-(2-(dimethylamino)ethyl)aniline analogue 24j was due to the fact the 2-Cl-Py did not transform to the OAt ether in situ and the subsequent hydrolysis step was very sluggish. We postulate that the presence of the more basic N,N,-dimethylaminoethyl side chain (pKa ≈11) must prevent

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• ], producing two different modes of binding: pH-dependent and salt-dependent binding mechanisms. In a pH-dependent binding mechanism, an overall proton is either released or taken up during the protein interaction due to the binding-induced pKa shift of acidic or basic amino acids present at the complex

Styryl-based new organic chromophores bearing free amino and azomethine groups: synthesis, photophysical, NLO, and thermal properties

• Anka Utama Putra,
• Deniz Çakmaz,
• Nurgül Seferoğlu,
• Alberto Barsella and
• Zeynel Seferoğlu

Beilstein J. Org. Chem. 2020, 16, 2282–2296, doi:10.3762/bjoc.16.189

• pKa determination of 8 in aqueous solution The pH value of aqueous systems is important to maintain the physiological stability, both inside and outside a living organism. The hydroxide anion plays a special and critical role in the ecosystem. Therefore, the necessity to develop new pH sensors is

• was accompanied by darkening purple color shifts of the solutions with increased pH value. However, the slight increase in the fluorescence was hardly noticeable below 365 nm UV light as is shown in Figure 8. The pKa of 8 was calculated by using a spectrophotometric method and was 8.22 ± 0.03 (Figure

• stated earlier for the UV–vis absorption study at room temperature (25 °C). All photographs were taken using a SONY RX100 pocket camera with ISO values of 200 and variable aperture at “Program Auto” mode. pKa Determination of dye 8 The solubility of dye 8 in deionized water was investigated by studying

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• GCP moiety by itself does not interact with DNA/RNA but, if combined with oligomers [15][16] or attached to the aryl moiety containing at least two aromatic rings [17], it will ensure efficient DNA/RNA binding. Moreover, due to the weakly acidic pKa = 6 of GCP, interactions and consequently

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• a positive impact on the biological absorption and distribution. Moreover, C–H/C–F substitution strongly decreases the basicity of neighboring amines (and lowers the pKa by a similar increment) due to the σ-inductive effect of F. This results in i) a higher oral bioavailability [19], ii) a potential

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• ]. Apart from a slight shape/volume alteration caused by the significant change in bond angles and the deletion of two hydrogen atoms, this bioisosteric modification also usually results in improved metabolic stability, increased rigidity and, due to its electron-withdrawing nature, pKa modulation of

• -position (5), the introduction of the oxetanyl group leading to 6 induces a significant pKa(H) decrease. While the reduction in logP is still observed, the larger proportion of unprotonated substrate leads to a logD7.4 increase. Aliphatic fluorination can also be employed to decrease lipophilicities [6][19

Azo-dimethylaminopyridine-functionalized Ni(II)-porphyrin as a photoswitchable nucleophilic catalyst

• Jannis Ludwig,
• Julian Helberg,
• Hendrik Zipse and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2119–2126, doi:10.3762/bjoc.16.179

• , spiropyranes, and stilbenes [2]. Diarylethenes were reported in the context of photoswitchable catalysis as inhibitors of the Karstedt´s catalyst [3] and for pKa modulation in acid–base-controlled processes [4]. Molecular motors for stereodivergent anion binding catalysis [5], azopeptides for the acetylation

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• ]. Firstly, in comparison to simple guanidinium cations 2 (pKa 12.5) and ammonium cations 3 (pKa 10.5), the Schmuck cation has a lower pKa value of 7 to 8 due to the increased acidity of acylguanidiniums, which favors the formation of stronger hydrogen-bonded ion pairs (Figure 1, magenta part). Secondly, the

• an endosomal pathway. The low pKa value of the four GCP moieties could result in an improved buffering capacity, which could facilitate endosomal escape by the proton-sponge effect [28]. Significant inhibition of DNA transfection by bafilomycin (a macrolide antibiotic that can block the endosomal