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

A new synthetic protocol for coumarin amino acid

• Xinyi Xu,
• Xiaosong Hu and
• Jiangyun Wang

Beilstein J. Org. Chem. 2013, 9, 254–259, doi:10.3762/bjoc.9.30

• similar extinction coefficients and quantum yields as compound 1a, according to the literature [20][21]. However, their pKa values are significantly different from those of 1a, as shown in Table 3. The pKa values are calculated from the absorbance at 360 nm at different pH values illustrated in Figure 3

• , by using the Henderson–Hasselbalch equation. The halogenation of 1a at the 6-position decreases the pKa value, which makes compounds 1b and 1c good substitutes for 1a in fluorescent labeling and other investigations in biological systems. Screening for the synthetase/tRNA pair for 1b and 1c is under

• . The fluorescent group wouldn’t cause significant perturbations on proteins due to its small size, thus, it greatly extends the scope of fluorescence imaging techniques. Compound 1a has a pKa of 7.8 and only its conjugate base is fluorescent. This limits its usage in the fluorescence imaging in vivo

Inclusion of the insecticide fenitrothion in dimethylated-β-cyclodextrin: unusual guest disorder in the solid state and efficient retardation of the hydrolysis rate of the complexed guest in alkaline solution

• Dyanne L. Cruickshank,
• Natalia M. Rougier,
• Raquel V. Vico,
• Susan A. Bourne,
• Elba I. Buján,
• Mino R. Caira and
• Rita H. de Rossi

Beilstein J. Org. Chem. 2013, 9, 106–117, doi:10.3762/bjoc.9.14

• hydroxide ions in basic media; therefore, when calculating the NaOH concentration required for preparation of the solutions it is necessary to take this fact into account. Since we did not find values for the pKa of DIMEB in the literature, we used the pKa value of β-CD, viz. 12.20 [29][30]. Chemical

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• on the basis of in vitro cruzain activity (Table 1). Nor could the trends be explained as an effect of lysosomotropism, since enhanced potency was observed only for the 4-pyridyl analogues and not for 2- or 3-pyridyl analogues, which have similar pKa values. Instead, we considered that additional

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• -deficient pyridine ring. The pKa value of 7-azaindole is ~4.9, and it undergoes self-association through hydrogen-bonding to form a dimer in solution and phototautomerizes by an excited-state double-proton-transfer (ESDPT) process [1][48]. In the presence of copper or palladium catalysts azaindole undergoes

Self-assembled organic–inorganic magnetic hybrid adsorbent ferrite based on cyclodextrin nanoparticles

• Ângelo M. L. Denadai,
• Frederico B. De Sousa,
• Joel J. Passos,
• Fernando C. Guatimosim,
• Kirla D. Barbosa,
• Ana E. Burgos,
• Fernando Castro de Oliveira,
• Jeann C. da Silva,
• Bernardo R. A. Neves,
• Nelcy D. S. Mohallem and
• Rubén D. Sinisterra

Beilstein J. Org. Chem. 2012, 8, 1867–1876, doi:10.3762/bjoc.8.215

• -Ni/Zn/βCD presented smaller particles and a more homogeneous particle size distribution. Higher porosity for this MHM compared to Fe-Ni/Zn was observed by Brunauer–Emmett–Teller isotherms and positron-annihilation-lifetime spectroscopy. Based on the pKa values, potentiometric titrations demonstrated

• ferrite surfaces. It can also be observed that the potentiometric curve for Fe-Ni/Zn/βCD exhibits at least four transitions, two in addition to the pure Fe-Ni/Zn. The pKa values of the ferrites were calculated by using the Henderson–Hasselbalch Equation 1, at the point where [A−] = [HA] [36]: Transitions

• at pKa 6.5 and 13.5 were attributed to the ionization of ferrite groups in the MHM system, since Fe-Ni/Zn also presented close transition values (pKa 6.5 and 12.6). Thus, transitions at pKa 5.5 and 9.4 in the Fe-Ni/Zn/βCD were attributed to the ionization of βCD primary and secondary hydroxy groups

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• the physicochemical properties of imidazo[5,1-c][1,2,4]triazine-3,6-dione derivatives we determined water-solubility, log P, and pKa values for compound 25 as a representative of this new class of heterocyclic compounds. Water solubility at physiological pH of 7.4 was found to be 47 µg/mL, which is a

• suitable range for perorally active drugs. A pKa value of 10.0, and a logP value of 3 was determined. Thus, the molecule will be uncharged under physiological conditions and the logP value is in a range which allows us to predict oral bioavailability [29]. Conclusion In conclusion, we have designed and

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• ) (Figure 2). All of these screened catalysts are bifunctional compounds possessing hydrogen-bonding donor and acceptor moieties. Catalysts based on thiourea and squaramide differ from each other in their possible hydrogen-bond angles, rigidity of conformation, and pKa values [20]. Although the two

Cation affinity numbers of Lewis bases

• Christoph Lindner,
• Raman Tandon,
• Boris Maryasin,
• Evgeny Larionov and
• Hendrik Zipse

Beilstein J. Org. Chem. 2012, 8, 1406–1442, doi:10.3762/bjoc.8.163

• Cation affinity values are important guidelines for the reactivity of Lewis and Brønstedt bases [1][2][3]. While proton affinity numbers (either as gas phase proton affinities or as solution phase pKa values) have been used for a long time in quantitative approaches to describe base-induced or base

Conformational analysis, stereoelectronic interactions and NMR properties of 2-fluorobicyclo[2.2.1]heptan-7-ols

• Fátima M. P. de Rezende,
• Marilua A. Moreira,
• Rodrigo A. Cormanich and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2012, 8, 1227–1232, doi:10.3762/bjoc.8.137

• steric effect, but it suppresses adventitious metabolism, influences the pKa of functional groups, and alters solution conformation [12]. In this context, conformational screening and theoretical evaluation of 2-fluorobicyclo[2.2.1]heptan-7-ols (2-fluoronorbornan-7-ols, compounds 5–8 in Figure 1

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

• Kalicharan Chattopadhyay,
• Erik Fenster,
• Alexander J. Grenning and
• Jon A. Tunge

Beilstein J. Org. Chem. 2012, 8, 1200–1207, doi:10.3762/bjoc.8.133

• nucleophiles [45][46][47][48][49][50][51][52][53][54][55]. In this realm, we [53][55] and others [54] have focused efforts on catalyzing benzylic substitutions with less-stabilized (DMSO pKa ~ 20–30) nucleophiles through decarboxylative coupling. In the present context, we hypothesized that a broad diversity