Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• compounds in the 1930s and 1940s [22][23]. It is a strong acid (pKa ≈ 0.5), quite volatile (bp. 72 °C) and miscible with water, fluorocarbons and most organic solvents [22]. In the late 1940s and throughout the 1950s, trifluoroacetic acid and trifluoroacetic anhydride were the subjects of a number of

• acids were recrystallized from suitable solvents such as acetone, lower alcohols and H2O. Acylation reactions in MeSO3H are more vigorous and exothermic than in CF3CO2H since MeSO3H (pKa ≈ −2) is a stronger acid than CF3CO2H (pKa ≈ 0.5). Their densities are the same (1.48 g/mL at 25 °C), but the melting

• acyl chlorides. The acylating activity of the medium was then fortified by the addition of trifluoromethanesulfonic acid (CF3SO3H), one of the strongest of all acids known (pKa ≈ −5.5), comparable to, or exceeding perchloric and fluorosulfonic acid (although the ordering of acidities is highly

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• , the tumor cells express pro-angiogenic factors including growth factors such as the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and enzymes such as cyclooxygenase 2 (COX-2) and protein kinase A (PKA) as well as signaling molecules such as integrins. The evoked cascade

TEMPO-derived spin labels linked to the nucleobases adenine and cytosine for probing local structural perturbations in DNA by EPR spectroscopy

• Dnyaneshwar B. Gophane and
• Snorri Th. Sigurdsson

Beilstein J. Org. Chem. 2015, 11, 219–227, doi:10.3762/bjoc.11.24

• ] showed one hydrogen bond, located between N6 of TA and N3 of cytidine (Figure S2B, Supporting Information File 1). If TA is protonated on N1 to form TAH+, it could form a wobble-pair with C [47][83] (Figure 3A), which would be expected to decrease the mobility of the spin label. The apparent pKa of the

Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

• Bin Yin,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2015, 11, 85–91, doi:10.3762/bjoc.11.12

• rather low yields (Table 3, entry 5). The longer electrolysis caused the formation of complicated products. This result is quite different from the case of 1b and 1d (Table 2, entry 1 and Table 3, entry 1). Such different anodic behavior may be attributable to different pKa values of the α-proton of the

A facile synthesis of functionalized 7,8-diaza[5]helicenes through an oxidative ring-closure of 1,1’-binaphthalene-2,2’-diamines (BINAMs)

• Youhei Takeda,
• Masato Okazaki,
• Yoshiaki Maruoka and
• Satoshi Minakata

Beilstein J. Org. Chem. 2015, 11, 9–15, doi:10.3762/bjoc.11.2

• organic bases like DABCO (pKa 8.93 in DMSO [32]) and DBU (pKa 23.9 in MeCN [33]) gave a lower yield (32%) and no product, respectively (Table 1, entries 14 and 15). As results, the use of the moderately weak organic base 2,6-lutidine (pKa 6.72 in water [34]) successfully afforded 2a in high yield (Table 1

Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

• Lisa Markenstein,
• Antje Appelt-Menzel,
• Marco Metzger and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 3087–3096, doi:10.3762/bjoc.10.325

• 2 d reaction time. The decreasing yield was rationalized by the increasing consumption of propargyl glycidyl ether by hydrolysis with increasing OH− concentration. On the other hand, due to the low pKa ≈ 12 of polyglucanes, deprotonation still takes place at very low concentrations of OH− [42][43

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study

• Monica Ferro,
• Franca Castiglione,
• Carlo Punta,
• Lucio Melone,
• Walter Panzeri,
• Barbara Rossi,
• Francesco Trotta and
• Andrea Mele

Beilstein J. Org. Chem. 2014, 10, 2715–2723, doi:10.3762/bjoc.10.286

• two gels loaded with IP – CDNSEDTA 1:4 and CDNSEDTA 1:8 – were 6.9 and 6.5, respectively. Taking into account the literature pKa values [33] of EDTA for the ionization of the four COOH groups ( pKa1 = 0.0, pKa2 = 1.5, pKa3 = 2.0, pKa4 = 2.7), the contribution of the two NH+ groups (pKa5 = 6.1, pKa6

• = 10.4) and the pKa value of IP in its acid form (4.91), it is reasonable assuming that the majority of the COOH groups present in our systems are, in the pH interval of our preparations, present in the COO− form and that one NH+ group is significantly contributing. As a consequence, an overall negative

Superoxide chemistry revisited: synthesis of tetrachloro-substituted methylenenortricyclenes

• Basavaraj M. Budanur and
• Faiz Ahmed Khan

Beilstein J. Org. Chem. 2014, 10, 2531–2538, doi:10.3762/bjoc.10.264

• . The olefin-substituted compound 3p (Table 1, entry 16) underwent a smooth reaction to afford nortricyclene 5m (Scheme 2). The cyclooctane-fused adducts 3o/4o (Table 1, entry 15) afforded exclusively the elimination product 6c in excellent yield. As the pKa of the conjugate acid of the superoxide ion

Second generation silver(I)-mediated imidazole base pairs

• Susanne Hensel,
• Nicole Megger,
• Kristina Schweizer and
• Jens Müller

Beilstein J. Org. Chem. 2014, 10, 2139–2144, doi:10.3762/bjoc.10.221

• attempt to increase the stability of the imidazole–Ag(I)–imidazole base pairs, additional shielding of the central silver(I) ions could be accomplished by introducing methyl groups on the imidazole moieties. A comparison of the pKa values [36] of 1-methylimidazole (pKa = 7.21), 1,2-dimethylimidazole (pKa

• = 8.22) and 1,4-dimethylimidazole (pKa = 7.75) indicates that this modification is also expected to slightly increase the basicity of the ligand, thereby also contributing to the formation of a more stable metal complex. Results and Discussion Synthesis and characterization of the nucleosides Scheme 2

• the two hydroxy functions with the dimethoxytrityl and the 2-cyanoethyl-N,N-diisopropylphosphoramidite moieties, finally resulting in the formation of 4a/4b suitable for automated solid-phase oligonucleotide synthesis. The pKa values of the free nucleosides 2a/2b were determined by pD-dependent 1H NMR

Photorelease of phosphates: Mild methods for protecting phosphate derivatives

• Sanjeewa N. Senadheera,
• Abraham L. Yousef and
• Richard S. Givens

Beilstein J. Org. Chem. 2014, 10, 2038–2054, doi:10.3762/bjoc.10.212

• the lack of product formation for 2-hydroxy-6-trifluoromethylnaphthylene photo-dehydrofluorination reported by Seiler and Wirz [51]. For the 1,5-HNA acetate, the less reactive (higher pKa) of the leaving OAc group of 27 vs DEP, fluorescence decay and reversible ESIPT processes are major factors

Photo, thermal and chemical degradation of riboflavin

• Muhammad Ali Sheraz,
• Sadia Hafeez Kazi,
• Sofia Ahmed,
• Zubair Anwar and
• Iqbal Ahmad

Beilstein J. Org. Chem. 2014, 10, 1999–2012, doi:10.3762/bjoc.10.208

• identified as 2,3-butanedione and is produced from the side-chain of RF by the action of singlet oxygen. Its formation is greatly affected by the pH of the medium as the highest content of this compound was found at pH 6.5, followed by 4.5 and 8.5 [59]. RF is highly sensitive to pH and has pKa values of 1.7

• reaching a maximum at pH 10. This is probably due to the higher reactivity of the flavin triplet in this region [24] (Figure 3). The slight decline above pH 10 is due to the anion formation (pKa 10.2). In acidic region, the slight increase (about 2 folds) in the rate of degradation of RF at pH 3 is due to

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• stoichiometry (preQ1:TFA) based on 1H NMR spectra and consideration of pKa values. However, it is noteworthy that a crystal structure of the preQ1·TFA salt that was crystallized from saturated aqueous solution showed the co-existence of mono- (N(C'7)) and dications (N(C'7), N3) in the crystal [11]. The

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• nucleoside-derived allenes 97 (the uridine example shown), and a number of amines 100 (four equivalents, Scheme 41). The polyfunctional products 101 were obtained with excellent (Z)-stereoselectivity. The authors noticed a pronounced relationship between pKa of the amine and the isolated yield of the product

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• (Figure 3). This O,C-digeranyl geminal bisphosphonate was expected to preserve a V-like structure very similar to that of DGBP. However, the presence of an oxygen substituent on the geminal carbon should lower the pKa of bisphosphonate 6 relative to that of compound 5, which might enhance its similarity

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• -carbon E-ring and a pyridine F-ring. Cyclopamine inhibits the 7-transmembrane protein smoothened from converting into its active form [18][19]. Without active smoothened, protein kinases like PKA, GSK3β, and CK1ε phosphorylate the transcription factors Gli2 and Gli3, thereby creating binding sites for

A promising cellulose-based polyzwitterion with pH-sensitive charges

• Thomas Elschner and
• Thomas Heinze

Beilstein J. Org. Chem. 2014, 10, 1549–1556, doi:10.3762/bjoc.10.159

• ). Moreover, the question arises how the pKa value is influenced by further substituents. Therefore, the acidity of the ammonium groups of ω-aminoethylcellulose carbamate [23], (3-ethoxy-3-oxopropyl)(2-aminoethyl)cellulose carbamate 6 and the polyzwitterion 7a were compared. Polycation 6 was titrated forth

• and back in range from pH 4.3 to 10 (Figure 3). The rising point of inflection, representing the pKa value of the amino group (9.0), was determined by the first derivative of the curve (dpH/dV) that yields the minimum. To obtain the pKa value of the amino group in the polyzwitterionic molecule the

• titration curve of 7a could be considered. In Figure 4 the minimum of the first derivative at 340 μL indicates a pKa value of 9.7. Thus, the pKa increases from 8.6 [23] to 9.0 if the ester moiety is present within the polymer chain and, moreover, the value increases to 9.7 for cellulose carbamate containing

Why a diaminopyrrolic tripodal receptor binds mannosides in acetonitrile but not in water?

• Diogo Vila-Viçosa,
• Oscar Francesconi and
• Miguel Machuqueiro

Beilstein J. Org. Chem. 2014, 10, 1513–1523, doi:10.3762/bjoc.10.156

• . In the case of the first generation amino groups, they are much closer to each other, with limited conformational freedom, resulting in much lower pKa values. The small number of titrable sites in the receptor allows us to analyze in detail the population of each possible microstate. In particular

• observations are completely analogous to the described above. As expected, geometrically constrained titrable sites show strong interactions due to electrostatic repulsion which results in shifted pKa values and in some forbidden (not sampled) protonation states. These results illustrate the usefulness of the

• force field. The model compound pKa value used (10.64 for all equivalent amino groups) is the pKa of the dimethylamine [54]. It was used a dielectric constant of 2 for the solute and 80 for the solvent. Grid spacing of 0.1 nm, in the coarser calculation, and 0.025 nm, in the focusing procedure, were

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards ‘clickable’ biodegradable polylactide

• Quanxuan Zhang,
• Hong Ren and
• Gregory L. Baker

Beilstein J. Org. Chem. 2014, 10, 1365–1371, doi:10.3762/bjoc.10.139

• source of acetylene building moiety; and 2) basic reaction conditions involving a low pKa (<24) to avoid the interruption of the ethynyl proton (pKa ~24) while introducing the acetylene moiety. Propargyl tosylate, prepared from propargyl alcohol and tosyl chloride, is a safe analogue of propargyl bromide

• with low cost. Malonate has a low pKa of ~13 and can be easily deprotonated and alkylated by mild bases such as sodium/potassium alkoxides without deprotonating a terminal alkyne. Conveniently, both malonate and propargyl alcohol are commercially available in bulk quantities. Herein, we report one

• Na2SO3 with ether (Table 2). Apparently, acid 1 precipitated as its sodium salt from ether via an acid–base reaction with Na2SO3 (pKa of 1: ~3.8 [45]; pKa of H2SO3: 1.9, 7.2). When reductant Na2S2O3 was added to an ether solution of acid 1, a yellow solid mixture containing both acid 1 and sulfur was

Substitution effect and effect of axle’s flexibility at (pseudo-)rotaxanes

• Friedrich Malberg,
• Jan Gerit Brandenburg,
• Werner Reckien,
• Oldamur Hollóczki,
• Stefan Grimme and
• Barbara Kirchner

Beilstein J. Org. Chem. 2014, 10, 1299–1307, doi:10.3762/bjoc.10.131

• also witnessed for diketopiperazine-based amide rotaxanes [57]. In Table 2, also the Hammett σ parameters are given. These substituent parameters [43] are the difference of the pKa values of substituted and non-substituted benzoic acids, they can be correlated with the interaction energies resulting in

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• mechanism proceeding by radical processes. Indeed, the use of UV irradiation or radical initiators in the absence of trialkylamine was found to be unsuccessful to produce phosphoramidates. Recently, Krutikov et al. [9] have reported that hexahydroazepine (a secondary amine with a pKa of 11.1 (Scheme 3-iii

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

• Michael J. Burns,
• Thomas O. Ronson,
• Richard J. K. Taylor and
• Ian J. S. Fairlamb

Beilstein J. Org. Chem. 2014, 10, 1159–1165, doi:10.3762/bjoc.10.116

• high acidity of hydroxypyrones such as 3 (Scheme 1; R1 = H, pKa = 4.94 [13]), they would appear to be ideal coupling partners in the Mitsunobu reaction. We recently published an example of the Mitsunobu reaction using the compound 4-hydroxy-6-methyl-2-pyrone (3a) [14]. To the best of our ability, we

On the mechanism of photocatalytic reactions with eosin Y

• Michal Majek,
• Fabiana Filace and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2014, 10, 981–989, doi:10.3762/bjoc.10.97

• eosin Y solutions prompted us to further investigate this behaviour. The organic dye eosin Y can exist in four different structures in solution: the spirocyclic form EY1, the neutral EY2, the monoanionic EY3, and the dianionic form EY4 (Scheme 3). Eosin Y contains two relatively acidic protons (pKa 2.0

Polyglycerol-functionalized nanodiamond as a platform for gene delivery: Derivatization, characterization, and hybridization with DNA

• Li Zhao,
• Yuki Nakae,
• Hongmei Qin,
• Tadamasa Ito,
• Takahide Kimura,
• Hideto Kojima,
• Lawrence Chan and
• Naoki Komatsu

Beilstein J. Org. Chem. 2014, 10, 707–713, doi:10.3762/bjoc.10.64

• potentials of the ND-PG-BPP are roughly propotional to the pKa values of the side chains in these basic amino acids; His (6.0), Lys (10.5), and Arg (12.5). The positive surface charge of nanoparticles enables complexation with negatively charged DNA through electrostatic interaction. To analyze the DNA

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• that the lower electrophilicity of arylimines and the possible enamide conjugation could account for this. Furthermore, it was shown that the pKa of the carboxylic acid significantly influenced the reaction rates, in which TFA gave the best results (2 days vs. 5 days for benzoic acid). No