Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• pKa values. In both macrocycles the UV maxima are bathochromically shifted (273 to 301 nm) for 4 and 261 to 294 nm for 8 (Supporting Information File 1, Figure S1). Also, the pKa values are affected by the cyclization. In case of dU (9.3) a decrease to 8.7 [35] for 6 and further to 8.2 for cyclic dU 8

• is observed (Supporting Information File 1, Figure S2). This might go back to stacking interactions of the nucleobase and the triazole residue. A similar relationship exists in the dC series with values of 4.2 for dC and 3.0 for 1 [35]. In contrast the pKa for cyclic dC 4 (3.2) did not further

Dynamic light scattering studies of the effects of salts on the diffusivity of cationic and anionic cavitands

• Anthony Wishard and
• Bruce C. Gibb

Beilstein J. Org. Chem. 2018, 14, 2212–2219, doi:10.3762/bjoc.14.195

• titration with various halide salts. The fifteen salts studied were a matrix of the alkali metal cations Li+, Na+, K+, and Cs+ in combination with the halides F− through I−, the one omission being poorly soluble lithium fluoride (maximum solubility = 0.134 g mL−1). Unsurprisingly, given the pKa values of

• -solubilizing group. Although its pKa may not be optimal for deprotonation at neutral or physiological pH, its small size and relatively high free energy of hydration (−373 kJ mol−1) ensure that ion-pairing effects are not strong. This was further confirmed by 1H NMR spectroscopy (Supporting Information File 1

Cobalt-catalyzed nucleophilic addition of the allylic C(sp³)–H bond of simple alkenes to ketones

• Tsuyoshi Mita,
• Masashi Uchiyama,
• Kenichi Michigami and
• Yoshihiro Sato

Beilstein J. Org. Chem. 2018, 14, 2012–2017, doi:10.3762/bjoc.14.176

• species (Figure 1). However, the substrates employed have been restricted to allylarenes and 1,4-enyne, and 1,4-diene derivatives and α-olefins were totally unexplored. Therefore, the next challenge would be to use less reactive α-olefins (pKa value of 1-propene = 43). In this paper, we describe an

• 1-undecene (1a) but also 1-octadecene (1b) and 6-phenyl-1-hexene (1c) were tolerable to afford the corresponding products in around 70% yield with perfect branch selectivity (Figure 3). Although the allylic C(sp3)–H bond of α-olefins is weakly acidic (pKa value of 1-propene = 43), it is noteworthy

Rational design of boron-dipyrromethene (BODIPY) reporter dyes for cucurbit[7]uril

• Mohammad A. Alnajjar,
• Jürgen Bartelmeß,
• Robert Hein,
• Pichandi Ashokkumar,
• Mohamed Nilam,
• Werner M. Nau,
• Knut Rurack and
• Andreas Hennig

Beilstein J. Org. Chem. 2018, 14, 1961–1971, doi:10.3762/bjoc.14.171

• motifs for CB7. The unprotonated dyes show low fluorescence due to photoinduced electron transfer (PET), whereas the protonated dyes are highly fluorescent. Encapsulation of the binding motif inside CB7 positions the aniline nitrogen at the carbonyl rim of CB7, which affects the pKa value, and leads to a

• host-induced protonation and thus to a fluorescence increase. The possibility to tune binding affinities and pKa values is demonstrated and it is shown that, in combination with the beneficial photophysical properties of BODIPYs, several new applications of host–dye reporter pairs can be implemented

• investigate their complexation behaviour with CB7. The goal was to explore the suitability of this approach, the possibility to fine-tune binding constants with different anchor groups and to provide BODIPYs with different absorption and emission wavelengths as well as pKa values of the aniline substituent

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• initial broad long wavelength absorption (Figure 5A). The emission intensity of derivative 2c increased by a factor of 250 with decreasing pH value (Figure 5B). The pKa value of the protonated amine 2c in water was determined from the titration curve to be 3.1 which is in the same range as the ones of 9

• -(p-amino)phenylacridinium ions (pKa = 2.5–3.5) [49][50] and the dimethylaminophenyl-substituted benzo[b]quinolizinium ion [34] (pKa = 3.8). Photometric and fluorimetric DNA titrations of 9-(arylethynyl)benzo[b]quinolizinium derivatives 2a–d The interactions of the arylethynylbenzoquinolizinium

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• amides [64], no such vicinal effect created by a quaternary EWG of type >Nsp3H2+ [63] was detected in the piperazine P-1 linker of compounds 7b, 8 and 9, even in the case of the strongest proton donor, the trimesic acid (pKa = 3.12, 3.89 and 4.70). In addition, only in G-1 amino-dendron D-N

  NH the 1H

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• or secondary alcohols, while the nucleophilic species needs to be acidic [13] with a pKa < 11. Otherwise the azo reagent would compete with the acidic nucleophile and participate in the substitution reaction [14]. Various compounds comply with that condition: carboxylic acids, phenols, hydrazoic acid

• -chloroacetyl-D-glucose (30) as well as its galacto-configured analogue with the carboxylic acids 31–34 to obtain products 35–38 which are related to various pesticide agents (Scheme 6). Their results supported the theory that, along with an effect of the reaction temperature, an increase of the pKa of the

• authors state that the observed pKa effect is either due to the influence of the acidity of the employed acid on the reaction mechanism or results from the proton-catalyzed change of the anomeric ratio of the starting material 30 in solution. Very recently, anomeric phosphorylation via a Mitsunobu

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• substituent (3-quinolinyl nitrogen forming a hydrogen bond with a guanine amino group at the base of the minor groove) and a low pKa tail group. This drug was further selected for the treatment of Gram-positive bacteria Clostridium difficile infections and is currently in the phase II clinical trials

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• pseudorotation has almost exclusively used in mechanistic discussion of RNA cleavage. The stability of the phosphorane intermediate largely depends on its state of protonation. The first pKa value of the acyclic tetraalkoxy monohydroxy phosphorane has been estimated to be 8.6 for an equatorial hydroxy group and

• 13.5 for an apical group [22]. For a cyclic phosphorane derived from ethylene phosphate, the first pKa value is 7.9 and the second 14.3, both values referring to an equatorial hydroxy ligand [23]. Accordingly, both neutral phosphorane and its monoanion are present in significant amount at physiological

• activation free energy, ΔG‡ (or log k), against the change in standard free energy of the reaction, ΔGo (or log Keq). The latter quantity is often difficult, sometimes even impossible, to determine. For this reason, ΔG‡ (or log k) is more frequently plotted as a function of the pKa of the departing (or

An uracil-linked hydroxyflavone probe for the recognition of ATP

• Márton Bojtár,
• Péter Zoltán Janzsó-Berend,
• Dávid Mester,
• Dóra Hessz,
• Mihály Kállay,
• Miklós Kubinyi and
• István Bitter

Beilstein J. Org. Chem. 2018, 14, 747–755, doi:10.3762/bjoc.14.63

• , the spectra of UHF and UHF∙ATP were recorded at different pH values (Figure 4). Since the pKa value of the hydroxy group of the flavones is around 9 [54], no significant deprotonation should occur at pH 7.8. As can be seen in Figure 4, the excitation band of UHF around 400 nm is the same at each pH

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• (kcov/khydr), when reacting with an RNA primer. It will not be trivial to find such a leaving group, as the nucleophilicity of alcohols is quite similar to that of water, so that it is difficult to utilize the chemoselectivity toward reaction partners with different softness, pKa, or other structural

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