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

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

• substrate with formation of the corresponding azolium salt is highly favoured, as copper-coordinated alkynes are much more acidic than imidazolium or imidazolinium cations. For example, the pKa value of copper-coordinated propyne was calculated to be around 15 [13], whereas N,N-diarylimidazolium and N,N

• -diarylimidazolinium chloride salts have pKa values of about 19.8 to 21.1 and 20.7 to 21.5, respectively, for example pKa [1,3-bis(2,6-diisopropylphenyl)imidazolium chloride] = 21.1 ± 0.5 and pKa [1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride] = 21.5 ± 0.5 in aqueous solution at 25 °C [154]. In contrast to free

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• reactive compared to their non-stabilized counterparts, they tend to epimerize the existing chiral center of 1 a lot less, if at all (pKaH value of 69 in DMSO is 8.5 compared to the pKa value of Ph3(Me)PBr, which is 22.5) [109]. Another method to prepare α,β-unsaturated esters is the Horner–Wadsworth

• , e.g., triphenylphospine oxide. As with the Wittig reaction, the HWE reaction can also promote the epimerization of the α-proton (pKa of triethoxyphosphonoacetate in DMSO is 18.6) [109]. We have experienced this tendency especially with α-amino ketophosphonates [110], but there is also evidence that

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• structures will be introduced. The additional nitrogen atom in pyrimidine leads to a significantly reduced basicity when compared to simple pyridine (pKa[pyrimidine] = 1.1; pKa[pyridine] = 5.3) as well as a much more electron-deficient ring system. However, owing to the presence of two nitrogen atoms

Synthesis, characterization and luminescence studies of gold(I)–NHC amide complexes

• Adrián Gómez-Suárez,
• David J. Nelson,
• David G. Thompson,
• David B. Cordes,
• Duncan Graham,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2013, 9, 2216–2223, doi:10.3762/bjoc.9.260

• use of 1 equiv of aniline or 2-aminopyridine led to the isolation of complexes 2 and 3 respectively, in good yields after overnight reaction at room temperature. These results are consistent with the known pKa of [Au(OH)(IPr)] (30.3) [26]; the scope of this preparative route is, as with other

• deprotonation reactions with this building block, limited to substrates with a pKa lower than 30. Encouraged by these exploratory reactions, a series of (hetero)aromatic amines were employed to prepare the corresponding gold(I)–amide complexes. The desired complexes were obtained by reaction of [Au(OH)(IPr)] (1

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• found to be optimal, lie within a narrow range of pKa values. The authors suggested that TFA protonates the enone 83, thus accelerating the addition of the α-amino radical to the enone (84). The Nishibayashi group reported that α-amino radicals generated from a different class of amines, anilines 87

Gold-catalyzed regioselective oxidation of propargylic carboxylates: a reliable access to α-carboxy-α,β-unsaturated ketones/aldehydes

• Kegong Ji,
• Jonathan Nelson and
• Liming Zhang

Beilstein J. Org. Chem. 2013, 9, 1925–1930, doi:10.3762/bjoc.9.227

• rationalized by invoking inductive polarization of the C–C triple bond by the electronegative carboxy group. Such polarization could be revealed by calculated natural charges via natural population analysis [39] and corroborated by experimentally detectable properties such as pKa [40] and 13C NMR [41]. We

Coupling of C-nitro-NH-azoles with arylboronic acids. A route to N-aryl-C-nitroazoles

• Marta K. Kurpet,
• Aleksandra Dąbrowska,
• Małgorzata M. Jarosz,
• Katarzyna Kajewska-Kania,
• Nikodem Kuźnik and
• Jerzy W. Suwiński

Beilstein J. Org. Chem. 2013, 9, 1517–1525, doi:10.3762/bjoc.9.173

• research. The reaction does not take place without a base (Table 2, entry 2) or in the absence of copper catalyst (Table 2, entry 7). A parameter influencing chemical yields to a greater extent was the applied solvent/base system. Sodium hydroxide (pKa = 15.7) [41] and triethylamine (Et3N) (pKa = 10.9) [42

• reaction was carried out in methanol in the presence of other bases such as potassium carbonate (pKa = 10.33) [43] and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, pKa = 12) [44] (Table 3, entries 12,13). Although the pKa values were determined in water, they are usually in good agreement in other polar

• solvents scales [45]. Not surprisingly, the differences in pKa values of the bases are reflected in the results obtained. Very strong bases (DBU, NaOH) are needed for the reaction to take place. Although the reaction with DBU yielded a similar amount of product as NaOH, the latter was chosen as being of

Simple and rapid hydrogenation of p-nitrophenol with aqueous formic acid in catalytic flow reactors

• Rahat Javaid,
• Shin-ichiro Kawasaki,
• Akira Suzuki and
• Toshishige M. Suzuki

Beilstein J. Org. Chem. 2013, 9, 1156–1163, doi:10.3762/bjoc.9.129

• reaction efficiency in a porous PdO reactor apparently depends on the pH of the reaction solution, as given in Figure 6. The decrease of pH produced markedly better conversion. By considering the pKa of formic acid (3.5), the acid form (HCO2H) contributes to the reaction conversion better than basic

C–C Bond formation catalyzed by natural gelatin and collagen proteins

• Dennis Kühbeck,
• Basab Bijayi Dhar,
• Eva-Maria Schön,
• Carlos Cativiela,
• Vicente Gotor-Fernández and
• David Díaz Díaz

Beilstein J. Org. Chem. 2013, 9, 1111–1118, doi:10.3762/bjoc.9.123

• formation (Table 3, entries 1 and 7). It is important to remark that even vanillin or citronellal, which are also components of many foods, could be partially converted to nitroaldol products by gelatin (Table 3, entries 12 and 15). When nitroethane (pKa = 8.6) was used as the nucleophile instead of

• nitromethane (pKa = 10.2) the yield increased considerably (Table 3, entries 2, 6, 10 vs. 1, 5, 9, respectively), albeit without significant diastereoselectivity. Thus, acidity of the nitroalkane plays here a more important role than steric effects [28]. It is worth mentioning that control experiments in the

Use of 3-[¹⁸F]fluoropropanesulfonyl chloride as a prosthetic agent for the radiolabelling of amines: Investigation of precursor molecules, labelling conditions and enzymatic stability of the corresponding sulfonamides

• Reik Löser,
• Steffen Fischer,
• Achim Hiller,
• Martin Köckerling,
• Uta Funke,
• Aurélie Maisonial,
• Peter Brust and
• Jörg Steinbach

Beilstein J. Org. Chem. 2013, 9, 1002–1011, doi:10.3762/bjoc.9.115

• -fluoroaniline. The difference in the nucleophilicity of these three aromatic amines is reflected by the pKa values of their corresponding ammonium ions decreasing from 4.65 over 4.58 to 1.02 for 4-fluoroaniline, aniline, and 4-nitroaniline, respectively [36]. To achieve satisfactory conversion of the 18F

• nucleophilic amines such as 4-nitroaniline. The reason for the beneficial effect of potassium trimethylsilanolate on the sulfonylation reaction could be a partial deprotonation of the 4-nitroaniline as the basicity of siloxides is comparable to that of alkoxides [39]. A pKa value of 21 has been reported for

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• with NaOH gave a pKa of ~6.5) [26]. Under the conception of Blackburn, methylidynetrisphosphonic acid, HC(PO3H2)3, can be viewed as a “supercharged” mimic of pyrophosphoric acid (PPi) since the introduction of a third ionizable phosphonate (PO3H2) group into methylenebisphosphonic acid delivers

• heteroatom substituent at the bridged carbon atom permits both modulation of pKa values and hydrogen bonding, there is a need for profound study of α-functionalized trisphosphonate systems. Such compounds can be promising building blocks for the synthesis of false substrates or enzyme inhibitors involved in

Spectroscopic characterization of photoaccumulated radical anions: a litmus test to evaluate the efficiency of photoinduced electron transfer (PET) processes

• Maurizio Fagnoni,
• Stefano Protti,
• Davide Ravelli and
• Angelo Albini

Beilstein J. Org. Chem. 2013, 9, 800–808, doi:10.3762/bjoc.9.91

• decomposition of TCB takes place to a small extent with DABCO, but it is much more conspicuous with secondary amines and the only path with the stannane. Radical cations of secondary amines are rather acidic (pKa = 5.3 for Et2NH•+ [54]) and undergo both α-C–H and N–H deprotonation, the latter process being also

A facile, rapid, one-pot regio/stereoselective synthesis of 2-iminothiazolidin-4-ones under solvent/scavenger-free conditions

• Murugan Sathishkumar,
• Sangaraiah Nagarajan,
• Poovan Shanmugavelan,
• Murugan Dinesh and
• Alagusundaram Ponnuswamy

Beilstein J. Org. Chem. 2013, 9, 689–697, doi:10.3762/bjoc.9.78

• available in the literature. While one of these reports suggests that the pKa [17] of amines directs the regioselectivity, another investigation indicates that the chelating effect [18] of the substituent directs the regiochemical outcome. In both the reports, two regioisomeric 2-iminothiazolidin-4-ones are

Kinetics and mechanism of the anilinolysis of aryl phenyl isothiocyanophosphates in acetonitrile

• Hasi Rani Barai and
• Hai Whang Lee

Beilstein J. Org. Chem. 2013, 9, 615–620, doi:10.3762/bjoc.9.68

• , 1H, aliphatic), 7.01–7.43 (m, 15H, aromatic); 13C NMR (100 MHz, MeCN-d3) δ 118.59–131.20 (m, 18C; aromatic); 31P NMR (162 MHz, MeCN-d3) δ 3.62 (d, J = 8.6 Hz, 1P, P=O); GC–MS (EI, m/z): 325 (M+). Brönsted plots with X [log kH versus pKa(X)] of the reactions of Y-aryl phenyl isothiocyanophosphates

Electron and hydrogen self-exchange of free radicals of sterically hindered tertiary aliphatic amines investigated by photo-CIDNP

• Martin Goez,
• Isabell Frisch and
• Ingo Sartorius

Beilstein J. Org. Chem. 2013, 9, 437–446, doi:10.3762/bjoc.9.46

• . With Equation 2, the free energy of the relayed deprotonation can be estimated from the reduction potential Φred (DH•+) of the radical cation (see, Table 1, but taken relative to NHE instead of SCE), the pKa of the protonated amine (8.9 [43]), and the calculated heats of formation ∆Hf of D• (+208 kJ

• more excellently described by a single exponential, with the same implications for the mechanism as in the case of DABCO. The free energy for the deprotonation of the radical cation by the amine itself can again be calculated with Equation 2. The pKa value of is only known in aqueous diglyme, where it