High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• screening of bases, the pKa of the amine and alcohol groups present in compound 12 were given careful consideration in order to minimize C–O bond formation (Table 4). NaOH or KOH in ethanol gave low (<40%) conversion, whereas using K2CO3 in ethanol gave 82% conversion to HCQ (Table 4, entry 3). Attempts

Synthesis and stability of strongly acidic benzamide derivatives

• Frederik Diness,
• Niels J. Bjerrum and
• Mikael Begtrup

Beilstein J. Org. Chem. 2018, 14, 523–530, doi:10.3762/bjoc.14.38

• ) or trifluoroacetic acid (3) are not readily modified, and changing substituents on these acids will heavily impact their pKa value (Figure 1). In contrast, halogenated benzoic acid derivatives are easily functionalized through cross-coupling [4][5] or nucleophilic aromatic substitution reactions

• , J = 8.8 Hz, 2H), 3.80 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 169.5, 159.2, 142.0, 135.7, 131.8, 129.2, 127.9, 125.4, 120.4 (q, J = 325.3 Hz). 114.4, 55.2; 19F NMR (470 MHz, DMSO-d6) δ −79.57 (s); HRMS (TOF) m/z: [M − H]− calcd for C15H5F7N3O3S−, 358.0366; found, 358.0408. Acid strength (pKa) of

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• ), forming the so called bile salts, with slightly different properties (pKa, solubility) in comparison to the corresponding free acids [24][25]. These bile salts also lead to an increased retention in the intestine. The only economically viable resource of bile acids is the bovine bile, which must be

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• reactivity with this electron-poor 7i suggested that the pKa is crucial for this catalysis. Further modifications of the chloramphenicol skeleton with various protecting groups on the nitrogen at C-2 position and oxygen at C-3 did not improve the reaction but with lowered enantioselectivity (Table 1, entries

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• -pyridyl-substituted ylide-like intermediate 7aa showed the desired properties in terms of both reactivity and stability, whereas the 4-pyridyl group only displayed high reactivity. For alkylpyridines 7aa and 7c, our observations may be explained by Fraser’s measurements of the pKa values [69][70][79

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• induced polarity and significant pKa-value changes of neighboring groups [9][10] can lead to fluorine-specific interactions between substrate and enzyme binding sites as well as to an exclusion of the cleavage-relevant peptide bonds from the active site. Furthermore, our investigations show that

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• 12·DMF. Due to significant steric effects, the single bond C4–C11 is significantly elongated (1.567(2) Å), and two nitro groups in ortho-positions of the connected picryl fragment are rotated out of the plane of the benzene ring. Thus, reactions of ANBF with strong CH acids (pKa(H2O) 4–11) proceed

• without added base while in case of diethyl malonate (pKa(H2O) 13.3) and TNT (pKa(H2O) 13.6) the addition of one equivalent of Et3N is required. In the latter case the formation of the adducts proceeds through the attack of the anion on C7. All other CH acids used exist mainly in enol form in polar

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• example of such type of reaction was reported by Just and Hakimelahi in 1979 [49]. Their work was focused on the mono- or dichlorination of various carbon acids, in the pKa range between dialkyl malonate and methyl dichloroacetate, as well as certain nucleophiles, were reacted with

Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

• Marco Russo,
• Daniele La Corte,
• Annalisa Pisciotta,
• Serena Riela,
• Rosa Alduina and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2751–2763, doi:10.3762/bjoc.13.271

• larger and larger amount of AmCD is subtracted from the solution at the same time. Noticeably, because the pKa value reported for alginic acid is far below 4.0 [54], we can rule out that Alg is neutralized up to a significant extent under our experimental conditions. We verified that Alg alone does not

Binding abilities of a chiral calix[4]resorcinarene: a polarimetric investigation on a complex case of study

• Marco Russo and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2698–2709, doi:10.3762/bjoc.13.268

• ionizable sites (four sites per prolinylarene subunit) and 12 acidic hydrogens, keeping into account both the proline moieties and the phenolic groups [32]. One can reasonably expect that the proline subunits at the macrocycle’s upper rim are present in their zwitterionic form. On grounds of the pKa values

• (with methyl groups in place of the n-propyl groups at the methylene bridges), an average pKa value as large as 6.3 ± 1 per arene subunit has been estimated from titration curves, under the hypothesis that the four subunits behave equivalently [32]. In the latter case, the deprotonation of phenol groups

Metal-mediated base pairs in parallel-stranded DNA

• Jens Müller

Beilstein J. Org. Chem. 2017, 13, 2671–2681, doi:10.3762/bjoc.13.265

• the triplex represents a duplex of its own. Scheme 2a indicates how the A:T and G:CH+ Hoogsteen base pairs are formally derived from the respective base triples. As can be seen, the cytosine residue needs to be protonated to engage in this hydrogen-bonding pattern. Based on the pKa value of a cytosine

• residue within an oligonucleotide single strand of about 4.3 [42], it can be anticipated that this base pair is ideally stabilized under slightly acidic conditions. However, triple helices including a protonated cytosine are stable under physiological conditions, too. In this context, the apparent pKa

• < 2FurIC (pKa = 8.8, 7.9, and 7.3 for the respective nucleosides), which is identical to the trend in stabilization [72]. For all XIC-derived base pairs, parallel-stranded duplexes were obtained by enforcing reversed Watson–Crick base pairing. 1,N6-Ethenoadenine (εA) is an exocyclic etheno adduct of

Electron-deficient pyridinium salts/thiourea cooperative catalyzed O-glycosylation via activation of O-glycosyl trichloroacetimidate donors

• Mukta Shaw,
• Yogesh Kumar,
• Rima Thakur and
• Amit Kumar

Beilstein J. Org. Chem. 2017, 13, 2385–2395, doi:10.3762/bjoc.13.236

• our own research interest in developing stereoselective glycosylation methods, we decided to focus our attention on the synthesis of glycosides via cooperative catalysis. A highly reactive glycosyl donor for instance, O-glycosyl trichloroacetimidate, generally requires a pKa value less than 5 for

• activation at room temperature [32][33][34][35][36]. It is known from the literature that pyridinium salts exhibit pKa values of about 5.2 [37]. Of late, Berkessel et al. disclosed an elegant method, where different electron deficient pyridinium salts (expected pKa values less than 5) were used as a catalyst

• for the activation of glycals to provide stereoselective 2-deoxyglycosides with high yields [38]. Based on this fact, we anticipated that for electron-deficient pyridinium salts the pKa value would be further diminished in the presence of hydrogen-bonding cocatalysts such as thiourea derivatives. The

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• first pKa ranging from 1.1 to 2.3 and the second acidity which features a pKa ranging from 5.3 to 7.2 [11]. The values strongly depend on the electronic properties induced by the substituent R. It must be noted that due to the high polarity of the phosphonic acid function, the purification of phosphonic

• analogue) [11]. Meanwhile, the phosphonic acid derivatives are more acidic when compared to their carboxylic acid equivalents (1.9 to 2.9 units of pKa below for the first acidity of phosphonic acid derivatives) [11]. This property was used to design Brönsted acid catalysts that were used for the

• consistent with a protonation at the oxygen atom that is doubly bonded to the phosphorus atom leading to a phosphorus centered cation (the protonated trimethyl phosphate was characterized by a pKa of −3.6). These results, extrapolated to phosphonate, suggest that the protonation of the phosphonate would

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• and facilitated the interaction and mobility of substrates [31][32][33], and allowed the substrates to better interact in situ. Given that DIPEA did not afford high yields albeit being liquid and having a pKa of 3.02, smaller than the one of mPEG (pKa = 4.5–4.8), it suggests that solvation may play a

Mechanochemical N-alkylation of imides

• Anamarija Briš,
• Mateja Đud and
• Davor Margetić

Beilstein J. Org. Chem. 2017, 13, 1745–1752, doi:10.3762/bjoc.13.169

• deprotonation of the imides with pKa values at least within the range of 8.3–9.9 units [30] under ball milling conditions. Deprotonation of phthalimide in solution is usually carried out with the use of bases stronger than K2CO3 [31] and this difference in reactivity in comparison to solvent free conditions has

Direct catalytic arylation of heteroarenes with meso-bromophenyl-substituted porphyrins

• Alexei N. Kiselev,
• Olga K. Grigorova,
• Alexei D. Averin,
• Sergei A. Syrbu,
• Oskar I. Koifman and
• Irina P. Beletskaya

Beilstein J. Org. Chem. 2017, 13, 1524–1532, doi:10.3762/bjoc.13.152

• described in the arylation reactions. In this connection we considered it important to develop an alternative approach to heteroaryl-substituted porphyrins using catalytic arylation of easily accessible meso-(bromophenyl)porphyrins with heterocycles possessing “acidic” C–H bonds, such as benzoxazole (pKa

• 24.4), benzothiazole (pKa 27.3), and N-methylbenzimidazole (pKa 32.5) [30]. Starting mono- and di(p-bromophenyl)-substituted porphyrins 1 and 11 were synthesized according to a described procedure [31], their analogues 2, 10, 12 were obtained using essentially the same approach. Results and Discussion

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• aldehyde or ketone) making this center more electrophilic (Scheme 1) [3]. Secondly, the pKa value of the anomeric OH group (glucose pKa ≈ 12.5 [9] or 14 [10]) is several orders of magnitude lower than for the other hydroxy groups (pKa ≈ 16–18) [9][10] so a careful selection of the base should allow for the

• decasaccharide donors. Shoda and co-workers proposed the differential reactivity at the anomeric center (Scheme 24, glucose shown for convenience) can be explained by the lower pKa (≈12.5–14) of the C1–OH [9][10][77]. They believe that the base-promoted nucleophilic attack of the anomeric OH (either the α or β

Sugar-based micro/mesoporous hypercross-linked polymers with in situ embedded silver nanoparticles for catalytic reduction

• Qing Yin,
• Qi Chen,
• Li-Can Lu and
• Bao-Hang Han

Beilstein J. Org. Chem. 2017, 13, 1212–1221, doi:10.3762/bjoc.13.120

• absorption peak at 317 nm of observed for the neutral 4-NP solution, the absorption at 400 nm is attributed to the 4-nitrophenolate ion. The latter is generated through deprotonation of 4-NP (pKa = 7.15) upon the addition of NaBH4 [41]. As can be seen from Figure 5a, the absorption peak of the substrate

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• with hydroxylamine-O-sulfonic acid followed by the reaction with HBF4 according to a previously described method [30]. Salts 1b,c were prepared by direct N-amination of the corresponding pyridines with O-mesitylsulfonylhydroxylamine. In view of difficulties in obtaining experimental pKa values of

• different positions of pyridinium cations we carried out DFT calculations [31] at the M06-2X 6-31+G(d,p) [32] level of theory with SMD [33] solvation (Figure 1, see also Supporting Information File 1). As expected, in all cases the NH2 group is the most acidic. The NH2 group is usually ≈12–13 pKa units more

• acidic than α-C–H hydrogens. However, the difference in pKa of NH2 and CH3 groups of the 4-methyl-1-aminopyridinium cation is not so high and the NH2 group is only 2.7 units more acidic. 1-Aminopyridinium and 4-methyl-1-aminopyridinium cations have similar pKa values for NH2 and α-C–H groups. The 4

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

• Matthew A. Horwitz,
• Elisabetta Massolo and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2017, 13, 762–767, doi:10.3762/bjoc.13.75

• -carboxylic acid because of its relatively low pKa (compared with non-carboxylate substituted analogs) and the possibility of using an ester linkage as a tether. We found that the heretofore unknown dicyclohexylcarbodiimide (DCC) mediated coupling between para-quinols and 1,3-dithiane-2-carboxylic acid

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• in fact, epimerizing KRs bind their substrates in two distinct modes. In the first, which is only available to the substrate bearing the non-epimerized methyl center, the thioester and C-3-keto groups are aligned so that the pKa of the C-2 proton is suitably depressed, allowing facile catalysis by KR

(Z)-Selective Takai olefination of salicylaldehydes

• Stephen M. Geddis,
• Caroline E. Hagerman,
• Warren R. J. D. Galloway,
• Hannah F. Sore,
• Jonathan M. Goodman and
• David R. Spring

Beilstein J. Org. Chem. 2017, 13, 323–328, doi:10.3762/bjoc.13.35

• substituents initially seems counter-intuitive, as it might be predicted that these could attenuate the ortho-hydroxy’s ability to coordinate to the Cr centre. Although the effect appears to correlate with lowered pKa of this hydroxy group, moderate amounts of (Z)-product are generated when this group is

Spectral and DFT studies of anion bound organic receptors: Time dependent studies and logic gate applications

• Srikala Pangannaya,
• Neethu Padinchare Purayil,
• Shweta Dabhi,
• Venu Mankad,
• Prafulla K. Jha,
• Satyam Shinde and
• Darshak R. Trivedi

Beilstein J. Org. Chem. 2017, 13, 222–238, doi:10.3762/bjoc.13.25

• relative dependence of the anion concentration on the reacting species. Similarly, the rate constants have been calculated for R1 and R2 in the presence of fluoride. The lower order of magnitude of the rate constant in the presence of F− ions could be correlated to the pKa value of 3.2 (F− ion) in

• comparison with AcO− ion whose pKa value is 4.8. The time response of receptors R1 and R2 in the presence of AcO− ion is represented in Supporting Information File 1, Figures S17 and S18. The observed rate constants at different wavelengths for R1 and R2 are summarized in Table 2. 1H NMR titration studies To

Interactions between photoacidic 3-hydroxynaphtho[1,2-b]quinolizinium and cucurbit[7]uril: Influence on acidity in the ground and excited state

• Jonas Becher,
• Daria V. Berdnikova,
• Darinka Dzubiel,
• Heiko Ihmels and
• Phil M. Pithan

Beilstein J. Org. Chem. 2017, 13, 203–212, doi:10.3762/bjoc.13.23

• red-shifted absorption bands and causes a dual emisson, i.e., a combination of emission bands of the hydroxyquinolizinium and its deprotonated form. Whereas this compound is a weak acid in the ground state (pKa = 7.9), it has a strongly increased acidity in the excited state (pKa* = 0.4). As a result

• , the blue-shifted fluorescence of the hydroxyquinolizinium becomes dominant only under strongly acidic conditions. In addition, it is shown that 3-hydroxynaphtho[1,2-b]quinolizinium binds to cucurbit[7]uril (CB[7]) with moderate affinity (Kb = 1.8 × 104 M−1, pH 5) and that the pKa and pKa* values of

• acidity or basicity. In fact, it was shown that the pKa of organic acids and bases often shifts by orders of magnitude upon association with CB[n] [16][17][18][19][20][21][22][23][24], which may be used, e.g., to modify catalytic activity [6] or for sensing purposes [7]. Notably, the same effect was

Silyl-protective groups influencing the reactivity and selectivity in glycosylations

• Mikael Bols and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2017, 13, 93–105, doi:10.3762/bjoc.13.12

• electronegativity of the R group is probably also important; when more electropositive (as Si), the oxygen atoms become more electron rich and their repulsion becomes larger. Changing the conformation of a heterocycle has, as mentioned, been studied using the piperidine model system. The pKa of the corresponding

• the reactivity of glycosyl donors with the pKa of the corresponding piperidinium ions. Conformational change induced by bulky vicinal protective groups such as TBS, TIPS and TBDPS. The vicinal clash overrules the 1,3-diaxial interaction, which is less influenced by bulky silyl ethers as these can