New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• substantial dipole moment (≈4.5 D) almost aligned with the C5–H bond and the relatively high acidity of this position (pKa(DMSO) = 27–28, for the 1H-tautomer). These heterocycles, which are easily available from 1,3-cycloaddition of alkynes and azides, can both form strong C–H bonds with hydrogen bond

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• basicity of these purine nitrogen atoms, because N1 represents the major protonation site, followed by N7 and N3. This order is deduced from the macroscopic pKa values that were measured for adenine, 9-methyladenine, and adenosine [11]. Importantly, there is growing evidence that the pKa values of

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• calculated (total polar surface area; TPSA) and measured (pKa, log P/D and Pe) parameters are shown in Table 1. The lipophilicity of neutral species of naringenin and dracocephins A and B are 3.39, 2.52 and 2.39, respectively. Similarly to this lipophilicity trend, the TPSA value of (±)-naringenin is lower

• than dracocephins A and B, however, there is no difference between the calculated TPSA values of 2a–d and 3a–d. The pKa values of the three phenolic hydroxy groups of the evaluated compounds are quite similar and these are in the range of 6.5 and 12.0. Among these proton-dissociation constants, the

• lowest acidic pKa values are predominant in physiological environment, which is also indicated by the difference of log D values between pH 7.4 and pH 6.5. The blood–brain barrier (BBB) specific penetration of dracocephins isomers has also been studied by the PAMPA (parallel artificial membrane

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• recognition motif for PKA (cAMP-dependent protein kinase) that enables enzymatic phosphorylation. We have analyzed the pathway of amyloid formation and the influence of enzymatic phosphorylation on the different states along the conformational transition from random-coil to β-sheet-rich oligomers to

• binding [43]. Additionally, phosphorylation may be found to direct desired behaviors in the currently intensively studied area of amyloid-based biomaterials. In this report we show the use of the negatively charged phosphate group to control the aggregation process. Using PKA and ATP (adenosine

• Peptide model Peptide KFM6 follows a typical coiled-coil heptad repeat sequence and it includes five amino acids (-R-R-A-S-L-) in positions 20–24, in proximity to the C-terminus, that serve as the recognition motif for PKA. The crucial role of this recognition motif for efficient phosphorylation has long

Et₃B-mediated and palladium-catalyzed direct allylation of β-dicarbonyl compounds with Morita–Baylis–Hillman alcohols

• Ahlem Abidi,
• Yosra Oueslati and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2402–2409, doi:10.3762/bjoc.12.234

• optimized conditions (Table 1, entry 4), we examined the scope of the catalytic system, Et3B/ Pd(OAc)2/PPh3, for a wide range of 1,3-dicarbonyl compounds and related derivatives (pKa = 9–14) [29][31] using two typical MBH alcohols 1a and 1b. The results of this study are summarized in Table 2. Like diethyl

• malonate (2a), the malonate derivative 2b (pKa = 13) [29] similarly reacted with the allylic alcohol 1a in the presence of the catalytic system Pd(0)/Et3B to exclusively give the mono-allylated product 3a in 65% yield, whereas the same reaction with ethyl 3-cyano-3-oxopropanoate (2c, pKa = 10.7) [43] whose

Experimental and theoretical investigations into the stability of cyclic aminals

• Edgar Sawatzky,
• Antonios Drakopoulos,
• Martin Rölz,
• Christoph Sotriffer,
• Bernd Engels and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 2280–2292, doi:10.3762/bjoc.12.221

• of the conformational energy of the ring system and pKa values of the N-3 nitrogen atom. Conclusion: Cyclic aminals are stable compounds when not exposed to acidic media and their stability is mainly dependent on the conformational energy of the ring system. Therefore, for the preparation and work-up

• the test compounds, as protonation of the tetrahydroquinazoline system is expected to be an essential factor of hydrolysis induction. Theoretically, protonation might occur at the anilinic N-1, the aliphatic N-3 or by double protonation of N-1 and N-3. Therefore the pKa values of both nitrogens of the

• corresponding fragments. Therefore, compounds with a higher pKa value at the N-3 nitrogen might increase the hydrolysis sensitivity of these compounds due to their faster protonation, like for compound 9b. Computational studies as well as experimental data revealed that the formation of tetrahydroquinazolines

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• considered (Scheme 6). The quinolin-2-one 13 was predicted to be a more amenable alkylation partner than the THQ 14 due to the likely lower pKa of the amide proton. To assess this, 13 was reacted with NaH and 2-iodopropane in DMF at 80 °C overnight. However, 13 displayed a marked lack of reactivity towards

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• copper(I) acetate and sodium acetate as additional base in order to deprotonate the thiazolium salt 1b and to form the bisthiazolylidene copper(I) complex 2. Due to the relatively high acidity of the thiazolium precursor (pKa ≈ 18 [44]), a weak base such as sodium acetate yields small equilibrium

Flow carbonylation of sterically hindered ortho-substituted iodoarenes

• Carl J. Mallia,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

• , did not significantly change the isolated yield of 5. However, changing to the stronger base DBU (pKa in water at 25 °C = 13.5) [40] dramatically reduced the isolated yield (Table 1, entry 8). A wider temperature range was also investigated (Table 1, entries 9–11). This resulted in only a small

The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals

• Sonia L. Repetto,
• James F. Costello,
• Craig P. Butts,
• Joseph K. W. Lam and
• Norman M. Ratcliffe

Beilstein J. Org. Chem. 2016, 12, 1467–1475, doi:10.3762/bjoc.12.143

• is non-trivial [6][8][10][12][13]; and indeed the debate about the factors influencing the overall rate of reaction and the synchronicity of steps has yet to achieve consensus [11][14][15]. Factors such as solvent [13], catalyst pKa [9], –OR basicity [6][16][17], the kinetic anomeric effect [18], the

Reactivity studies of pincer bis-protic N-heterocyclic carbene complexes of platinum and palladium under basic conditions

• David C. Marelius,
• Curtis E. Moore,
• Arnold L. Rheingold and
• Douglas B. Grotjahn

Beilstein J. Org. Chem. 2016, 12, 1334–1339, doi:10.3762/bjoc.12.126

• ) have been shown to form an imidazolyl ligand (e.g., 2) after deprotonation with a basic proton-accepting nitrogen (Figure 1). We are unaware of reports on an experimentally determined pKa value of a PNHC imidazolidene complex, but looking at related derivatives, Isobe showed that a 2-palladated

• pyridine was 3.57 pKa units more basic than pyridine [9][10]. Considering reactions other than simple proton transfer, imidazol-2-yl complexes have recently been used to bind to a second transition metal [11]. Additionally, Cp*Ir complexes from our group [12] demonstrated heterolysis of the H–H bond of H2

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• for a few times without activity loss. However, a long reaction time (120 h) was needed to achieve good results, and the low yields for N-unprotected substrates could be explained by the fact that the amide NH (pKa in DMSO ≈18.5) is more prone to be activated by K2CO3 than MeCN (pKa = 25). The long

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• their pKa values (approximately 19 in DMSO) [19] are much higher, one exception being thioesters [20][21] and pyrazoleamides [22]. As an alternative, some specific heterocycles have been proposed as carboxylic acid surrogates. Examples of this type of heterocycles are oxazol-5-(4H)-ones (or azlactones

cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57

• isomerism; fluorine; pKa; proline; Introduction The sole genetically encoded secondary amino acid proline (Pro, 1) is known for its unique properties in biological systems. In particular, Pro residues are often found in the s-cis peptidyl-Pro conformation, due to the low energy difference between the s

• models. Data on Pro (1) and (4S)-trifluoromethylproline (3) is used for comparison. Results and Discussion Firstly, we determined the pKa of the ammonium group in the free amino acids (Table 1). Overall the values demonstrate a 0.9 pKa reduction upon introduction of the 3,4-double bond, and a 2.2 pKa

• , this, indeed, has an orientation close to the equatorial CF3-group placement in 3, and is not axial. Next, we determined the pKa of the carboxyl groups in N-acetyl amino acids for two rotameric forms separately (Table 1). All four compounds exhibited similar ΔpKa values [36][37]. Though, absolute

Interactions between 4-thiothymidine and water-soluble cyclodextrins: Evidence for supramolecular structures in aqueous solutions

• Vito Rizzi,
• Sergio Matera,
• Paola Semeraro,
• Paola Fini and
• Pinalysa Cosma

Beilstein J. Org. Chem. 2016, 12, 549–563, doi:10.3762/bjoc.12.54

• greater than 9, with a pKa of ca. 9 as described in [26]. Under the latter conditions, the S4TdR-main absorption band located at 337 nm in neutral medium shifted to 321 nm. Moreover, the high molar absorption coefficients (ε) evaluated in [26] suggested that the absorption band of S4TdR was probably

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• deuterium incorporation in the benzylic position of 16 and 3h through acid-catalyzed imine–enamine tautomerization is dependent on the strength of the acid used (Figure 1). The rate of deuterium incorporation in 2-benzylpyridine (16, pKa ≈ 5.2) is much faster when using TFA-d1 than with AcOH-d4 [34][35

• ]. With the less basic 2-benzyl-5-chloropyridine (3h, pKa ≈ 3.0) the difference is even more pronounced: Almost no deuterium incorporation could be detected using AcOH-d4 while the reaction ran smoothly using the stronger acid TFA-d1. From this we conclude that when the pyridine nitrogen becomes less

• basic and protonation by the acid thus becomes more difficult, using more equivalents of the acid or a stronger acid is needed to reach full conversion. When we compare the different pKa values of substituted pyridines we see that 2-benzylpyridine (16, pKa ≈ 5.2) is one of the most basic pyridines [34

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• of steroids, to determining hydrocarbon pKa values using electrochemistry. The lesson learned, and one I tried to put into practice in my independent career (see below), is that it is very much possible to run a research group focused in quite different areas of chemistry. With an NSF-NATO

Co-solvation effect on the binding mode of the α-mangostin/β-cyclodextrin inclusion complex

• Chompoonut Rungnim,
• Sarunya Phunpee,
• Manaschai Kunaseth,
• Supawadee Namuangruk,
• Kanin Rungsardthong,
• Thanyada Rungrotmongkol and
• Uracha Ruktanonchai

Beilstein J. Org. Chem. 2015, 11, 2306–2317, doi:10.3762/bjoc.11.251

• databank (3C6G), while the α-MGS structure was extracted from the International Union of Crystallography (KP2293) database, see Figure 1. According to the ChemAxon method [25][26][27], the calculated pKa of three hydroxy groups are 7.4 (O6), 7.8 (O3), and 8.2 (O5). For that reason, the α-mangostin was

Convenient preparation of high molecular weight poly(dimethylsiloxane) using thermally latent NHC-catalysis: a structure-activity correlation

• Stefan Naumann,
• Johannes Klein,
• Dongren Wang and
• Michael R. Buchmeiser

Beilstein J. Org. Chem. 2015, 11, 2261–2266, doi:10.3762/bjoc.11.246

• , emphasizing that nucleophilicity is crucial for successful polymerization. Furthermore, it is interesting to note that the six- and seven-membered NHCs do not show any reactivity here, in spite of being very strong bases. While for a compound like 6-iPr a pKa-value of 28.2 (aqueous solution, 25 °C) was found

• , the five-membered imidazolium derivative 5-Mes was determined to have a pKa-value of only 20.8 (which compares to 15–19 for typical alcohols; in turn, silanols are even more acidic than the corresponding alcohols) [28][29][30][31][32]. At the same time, 5Me-Me-CO2 successfully catalyzed PDMS-formation

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• , the addition of amino additives such as pyridine, morpholine, Et3N or DBU was shown to be detrimental to the G-HII-catalyzed dimerization of styrene (Table 2). Moderate to poor yields in stilbene 7’ were obtained and the value of the yields was correlated with the pKa of the couple ammonium/amine. An

Photoinduced 1,2,3,4-tetrahydropyridine ring conversions

• Baiba Turovska,
• Henning Lund,
• Viesturs Lūsis,
• Anna Lielpētere,
• Edvards Liepiņš,
• Sergejs Beljakovs,
• Inguna Goba and
• Jānis Stradiņš

Beilstein J. Org. Chem. 2015, 11, 2166–2170, doi:10.3762/bjoc.11.234

• [26][27]. Superoxide O2−• is a highly reactive molecule [26][28] and it acts as a strong Brönsted base removing a proton from substrates to an extent equivalent to that of the conjugate base with a pKa value of approximately 23 in water [29][30]. A number of weakly acidic organic compounds are

SmI₂-mediated dimerization of indolylbutenones and synthesis of the myxobacterial natural product indiacen B

• Nils Marsch,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2015, 11, 1700–1706, doi:10.3762/bjoc.11.184

• ][28]. Thus, the indole NH group (pKa about 21 in DMSO) should be able to serve as a stoichiometric proton source that, after β,β'-coupling, would convert one of the Sm(III) enolates to the ketone. Attack of the remaining Sm(III) enolate would lead to Dieckmann-type ring closure, followed by

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

• Mohamed Yacine Ameur Messaoud,
• Ghenia Bentabed-Ababsa,
• Madani Hedidi,
• Aïcha Derdour,
• Floris Chevallier,
• Yury S. Halauko,
• Oleg A. Ivashkevich,
• Vadim E. Matulis,
• Laurent Picot,
• Valérie Thiéry,
• Thierry Roisnel,
• Vincent Dorcet and
• Florence Mongin

Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160

• initio methods [50]. The pKa values for N-methylindole, N-methylpyrrole and N-(dimethylamino)pyrrole as CH acids in THF were experimentally determined by Fraser et al [51]. The latter are more related to our goals and were found to be in good agreement with those computed within the DFT framework

• weak CH acidic compounds while the pKa values in THF solution (Figure 5) covered a 28.8–45.0 span. These data allow the assignment of potential deprotonation sites in the investigated substrates. Also the correlation between gas-phase ΔGacid and the pKa(THF) values can be tracked. In all cases, the CH

• contrast, the regioselectivity observed in case of substrate 2a cannot be explained by the pKa values as the only reason. Otherwise, deprotonation would have been also observed at the 2 position of the indole ring. Whereas the azole nitrogen in 2a cannot coordinate a metal through its electron lone pair

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• -phenylamino-1-deoxy-D-manno-heptulose 10 were obtained as pure α-anomers in 77% and 24% yield, respectively (Scheme 3). The low yield of compound 10 may be explained by the low pKa value (4.62) of aniline compared to a pKa of 8.15 for propargylamine, the latter being clearly more efficient as a nucleophile

Highly selective palladium–benzothiazole carbene-catalyzed allylation of active methylene compounds under neutral conditions

• Antonio Monopoli,
• Pietro Cotugno,
• Carlo G. Zambonin,
• Francesco Ciminale and
• Angelo Nacci

Beilstein J. Org. Chem. 2015, 11, 994–999, doi:10.3762/bjoc.11.111

• times) was found to depend on the nucleophilic strength of the intermediate enolates, and ultimately on pKa values (reactivity scale: diethyl malonate pKa 13.5 > acetoacetate pKa 11.0 > acetylacetone pKa 8.9). As an example, diethyl malonate reacted with allyl methyl carbonate much faster than