Crystal and mol-ecular structure of 4-fluoro-1H-pyrazole at 150†K.

Only two 4-halo-1H-pyrazole crystal structures are known to date (chloro and bromo, the structure of 4-iodo-1H-pyrazole has not been reported yet). The triclinic structure of 4-fluoro-1H-pyrazole, C3H3FN2 (P ), reported here is not isomorphous with those of the chloro and bromo analogues (which are isomorphous, ortho-rhom-bic Pnma). To avoid sublimation during the measurement, diffraction data were collected at 150 K. Two crystallographically unique 4-fluoro-1H-pyrazole moieties linked by an N-H⋯N hydrogen bond are found in the asymmetric unit. Unlike the trimeric supra-molecular motifs found in the structures of the chloro and bromo analogues, 4-fluoro-1H-pyrazole forms one-dimensional chains by inter-molecular hydrogen bonding in the crystal.

Selective binding of anions by rigidified nanojars: sulfate vs. carbonate.

Selective binding and transport of highly hydrophilic anions is ubiquitous in nature, as anion binding proteins can differentiate between similar anions with over a million-fold efficiency. While comparable selectivity has occasionally been achieved for certain anions using small, artificial receptors, the selective binding of certain anions, such as sulfate in the presence of carbonate, remains a very challenging task. Nanojars of the formula [anion⊂{Cu(OH)(pz)}n]2- (pz = pyrazolate; n = 27-33) are totally selective for either CO32- or SO42- over anions such as NO3-, ClO4-, BF4-, Cl-, Br- and I-, but cannot differentiate between the two. We hypothesized that rigidification of the nanojar outer shell by tethering pairs of pyrazole moieties together will restrict the possible orientations of the OH hydrogen-bond donor groups in the anion-binding cavity of nanojars, similarly to anion-binding proteins, and will lead to selectivity. Indeed, by using either homoleptic or heteroleptic nanojars of the general formula [anion⊂Cun(OH)n(L2-L6)y(pz)n-2y]2- (n = 26-31) based on a series of homologous ligands HpzCH2(CH2)xCH2pzH (x = 0-4; H2L2-H2L6), selectivity for carbonate (with L2 and with L4-L6/pz mixtures) or for sulfate (with L3) has been achieved. The synthesis of new ligands H2L3, H2L4 and H2L5, X-ray crystal structures of H2L4 and the tetrahydropyranyl-protected derivatives (THP)2L4 and (THP)2L5, synthesis and characterization by electrospray-ionization mass spectrometry (ESI-MS) of carbonate- and sulfate-nanojars derived from ligands H2L2-H2L6, as well as detailed selectivity studies for CO32-vs. SO42- using these novel nanojars are presented.

Selective, Ambient-Temperature C-4 Deuteration of Pyrazole Derivatives by D2O.

A simple, inexpensive, and highly efficient procedure for the selective deuteration (up to >99% D atom %) of the C-4 position of pyrazole substrates activated by NH2 or OH groups at the C-3(5) position is reported. The deuteration reaction is carried out by simply dissolving the substrate in D2O or other deuterated protic solvents, either in the absence of a catalyst with heating, or under acidic catalysis at ambient temperature; the products are obtained by simple evaporation of the solvent.

Reaction of Amines with Aldehydes and Ketones Revisited: Access To a Class of Non-Scorpionate Tris(pyrazolyl)methane and Related Ligands.

The reaction of amines with aldehydes and ketones has been exploited for over 150 years to produce Schiff bases, one of the most popular classes of compounds in both organic and coordination chemistry. In certain cases, however, compounds other than Schiff bases have been reported to result from such reactions. After conducting a representative reaction under various different conditions and identifying several reaction intermediates by NMR spectroscopy, mass spectrometry and X-ray crystallography, we now report a unified picture that explains the scattered and often inconsistent results obtained with 3(5)-aminopyrazole derivatives and other related molecules. Acid catalysis, which is often employed in Schiff base synthesis, radically changes the course of reaction and leads to bis(pyrazol-4-yl)methane derivatives instead of the expected Schiff base products. The stoichiometry of the reaction is also found to be crucial for obtaining quantitative conversions. A total of 31 new compounds have been isolated and characterized as a result of this study, including a reaction intermediate, 2 Schiff bases, and 28 bis- or tris(pyrazol-3(4)-yl)methane ligands. The latter defines a new class of "non-scorpionate" ligands, with three nonchelating pyrazole moieties, as opposed to the well-known "scorpionate" tris(pyrazol-1-yl)-borate and -methane ligands.

Accessing the inaccessible: discrete multinuclear coordination complexes and selective anion binding attainable only by tethering ligands together.

Novel multimetallic copper pyrazolate complexes, inaccessible using simple pyrazole ligands due to competing, alternative structural motifs, can be obtained by locking pairs of pyrazole ligands together with ethylene tethers. Nanojars based on this tethered pyrazole ligand display unexpected total selectivity for the carbonate over the sulfate ion.

Sulfate-Incarcerating Nanojars: Solution and Solid-State Studies, Sulfate Extraction from Water, and Anion Exchange with Carbonate.

A series of 9 homologous sulfate-incarcerating nanojars [SO4⊂{Cu(OH)(pz)}n]2- (Cun; n = 27-33; pz = pyrazolate), based on combinations of three [Cu(OH)(pz)]x rings (x = 6-14, except 11)-namely, 6 + 12 + 9 (Cu27), 6 + 12 + 10 (Cu28), 8 + 13 + 8 (Cu29), 7 + 13 + 9 (Cu29), 8 + 14 + 8 (Cu30), 7 + 14 + 9 (Cu30), 8 + 14 + 9 (Cu31), 8 + 14 + 10 (Cu32), and 9 + 14 + 10 (Cu33)-has been obtained and characterized by electrospray-ionization mass spectrometry (ESI-MS), variable-temperature 1H NMR spectroscopy, and thermogravimetry. The X-ray crystal structure of Cu29 (8 + 13 + 8) is described. Cu32 and Cu33, which are the largest nanojars in this series, are observed for the first time. Despite extensive overlap at a given temperature, monitoring the temperature-dependent variation of paramagnetically shifted pyrazole and OH proton signals in 60 different 1H NMR spectra over a temperature range of 25-150 °C and a chemical shift range from 41 ppm to -59 ppm permits the assignment of individual protons in six different sulfate nanojars in a mixture. As opposed to ESI-MS, which only provides the size of nanojars, 1H NMR offers additional information about their detailed composition. Thus, nanojars such as Cu29 (8 + 13 + 8) and Cu29 (7 + 13 + 9) can easily be differentiated in solution. High-temperature solution studies unveil a significant difference in the thermal stability of nanojars of different sizes obtained under kinetic control at ambient temperature, and aid in predicting the structure of the Cu33 nanojar, as well as in explaining the absence of the Cu11 ring from the Cu6-Cu14 series. Anion exchange studies using sulfate and carbonate reveal that, although each anion is thermodynamically preferred by a nanojar of a certain size, the exchange of an already incarcerated anion is hampered by a substantial kinetic barrier. The remarkably strong binding of anions by nanojars allows for the extraction of highly hydrophilic anions, such as sulfate and carbonate, from water into organic solvents, despite their very large hydration energies.

From Ordinary to Extraordinary: Insights into the Formation Mechanism and pH-Dependent Assembly/Disassembly of Nanojars.

Nanojars are large (2 nm wide) anion-incarcerating coordination complexes of the composition [anion⊂{Cu(µ-OH)(µ-pz)}n] (n = 27-36), formed by the self-assembly of simple Cu(2+), HO(-), and pyrazolate (pz(-) = C3H3N2(-)) ions in the presence of certain anions with large hydration energy (e.g., CO3(2-), SO4(2-), PO4(3-), HPO4(2-)). Nanojars display spectacular chemical properties, such as unparalleled anion binding strength and, as shown herein, extraordinary resistance to extreme alkalinities (10 M NaOH). To shed light on the mechanism of the self-assembly process leading to these distinctive constructs, we employed an array of complementary techniques including mass spectrometry, pH titration, UV-vis and NMR spectroscopies, chemical synthesis, and single-crystal X-ray diffraction. In the reaction of Cu(NO3)2, pyrazole, NaOH, and Na2CO3 in tetrahydrofuran (THF), the first major intermediate is a trinuclear copper pyrazolate complex, [Cu3(µ3-OH)(µ-pz)3(NO3)2(H2O)], which was separately isolated and characterized. As the THF-insoluble NaOH slowly reacts, the nitrate ions are gradually precipitated out as NaNO3 and replaced by hydroxide ions. The resulting species, [Cu3(µ3-OH)(µ-pz)3(OH)x(NO3)3-x](-) (x = 1-3), have unstable terminal Cu-OH groups and react with each other to yield OH-bridged units, such as [Cu3(µ3-OH)(µ-pz)3(NO3)2]2(µ-OH) and then [{Cu3(µ3-OH)(µ-pz)3(µ-OH)2}x(NaNO3)y(Na2CO3)z] oligomers. The Cu3(OH)3(pz)3 repeating units of these oligomers have the same composition as the [Cu(OH)(pz)]n (n = 3x) nanojars and rearrange to the final products, Na2[CO3⊂{Cu(µ-OH)(µ-pz)}n] (n = 27, 29, 31), while eliminating the last amounts of NaNO3. pH titration, UV-vis monitoring, and chemical synthesis also confirm the formation of the trinuclear intermediate, followed by its clean transformation to nanojars. While displaying an unusual stability to high pH, nanojars are sensitive to acids stronger than water, a property exploitable for the recovery of the incarcerated anion. On lowering the pH, nanojars first break down to trinuclear complexes and finally to copper ions and pyrazole. This process is fully reversible, and nanojars are reassembled as pH is increased.

Adjacent Lone Pair (ALP) Effect: A Computational Approach for Its Origin.

The adjacent lone pair (ALP) effect is an experimental phenomenon in certain nitrogenous heterocyclic systems exhibiting the preference of the products with lone pairs separated over other isomers with lone pairs adjacent. A theoretical elucidation of the ALP effect requires the decomposition of intramolecular energy terms and the isolation of lone pair-lone pair interactions. Here we used the block-localized wavefunction (BLW) method within the ab initio valence bond (VB) theory to derive the strictly localized orbitals which are used to accommodate one-atom centered lone pairs and two-atom centered σ or π bonds. As such, interactions among electron pairs can be directly derived. Two-electron integrals between adjacent lone pairs do not support the view that the lone pair-lone pair repulsion is responsible for the ALP effect. Instead, the disabling of π conjugation greatly diminishes the ALP effect, indicating that the reduction of π conjugation in deprotonated forms with two σ lone pairs adjacent is one of the major causes for the ALP effect. Further electrostatic potential analysis and intramolecular energy decomposition confirm that the other key factor is the favorable electrostatic attraction within the isomers with lone pairs separated.

Tuning the structure and solubility of nanojars by peripheral ligand substitution, leading to unprecedented liquid-liquid extraction of the carbonate ion from water into aliphatic solvents.

Nanojars, a novel class of neutral anion-incarcerating agents of the general formula [Cu(II)(OH)(pz)]n (Cun; n = 27-31, pz = pyrazolate anion), efficiently sequester various oxoanions with large hydration energies from water. In this work, we explore whether substituents on the pyrazole ligand interfere with nanojar formation, and whether appropriate substituents could be employed to tune the solubility of nanojars in solvents of interest, such as long-chain aliphatic hydrocarbons (solvent of choice for large-scale liquid-liquid extraction processes) and water. To this end, we conducted a comprehensive study using 40 different pyrazole ligands, with one, two or three substituents in their 3-, 4- and 5-positions. The corresponding nanojars are characterized by single-crystal X-ray diffraction and/or electrospray-ionization mass spectrometry (ESI-MS). The results show that Cun-nanojars with various substituents in the pyrazole 4-position, including long chains, phenyl and CF3 groups, can be obtained. Straight chains are also tolerated at the pyrazole 3-position, and favor the Cu30-nanojar. Homoleptic nanojars, however, could not be obtained with phenyl or CF3 groups. Nevertheless, if used in mixture with the parent non-substituted pyrazole, sterically hindered pyrazoles do form heteroleptic nanojars. With 3,5-disubstituted pyrazoles, only heteroleptic nanojars are accessible. The crystal structure of novel nanojars (Bu4N)2[CO3⊂{Cu30(OH)30(3,5-Me2pz)y(pz)30-y}] (y = 14 and 15) is presented. We find that in contrast to the parent nanojar, which is insoluble in aliphatic solvents and water, nanojars with alkyl substituents are soluble in saturated hydrocarbon solvents, whereas nanojars based on novel pyrazoles, functionalized with oligoether chains, are readily soluble in water. Liquid-liquid extraction of carbonate from water under basic pH is presented for the first time.

Survival of the Fittest Nanojar: Stepwise Breakdown of Polydisperse Cu27-Cu31 Nanojar Mixtures into Monodisperse Cu27(CO3) and Cu31(SO4) Nanojars.

Nanojars are emerging as a class of anion sequestration agents of unparalleled efficiency. Dinegative oxoanions (e.g., carbonate, sulfate) template the formation of a series of homologous nanojars [Cu(OH)(pyrazolato)]n (n=27-31). Pyridine selectively transforms less stable, larger CO3(2-) nanojars (n=30, 31) into more stable, smaller ones (n=27, 29), but leaves all SO4(2-) nanojars (n=27-29, 31) intact. Ammonia, in turn, transforms all less stable nanojars into the most stable one and allows the isolation of pure [CO3(2-)⊂{Cu(OH)(pz)}27] and [SO4(2-)⊂{Cu(OH)(pz)}31]. A comprehensive picture of the solution and solid-state intricacies of nanojars was revealed by a combination of variable temperature NMR spectroscopy, tandem mass spectrometry, and X-ray crystallography.

Drastic Deprotonation Reactivity Difference of 3- and 5-Alkylpyrazole Isomers, Their I2-Catalyzed Thermal Isomerization, and Telescoping Synthesis of 3,5-Dialkylpyrazoles: The "Adjacent Lone Pair Effect" Demystified.

N-Protected 3-alkylpyrazoles are easily deprotonated by (n)BuLi at the 5-position of the aromatic ring, while the 5-alkyl isomers are completely unreactive under the same conditions. Using computational analysis, we reveal that electron pair repulsion within the deprotonated anion is not the reason behind the lack of reactivity of 5-alkylpyrazoles. Instead, diminished π-resonance and attractive electrostatic interactions within the pyrazole ring are responsible for the observed effect. A greener, telescoping alternative to the synthesis of 3,5-dialkylpyrazoles is presented.

Deprotonation of methyl-substituted, five-membered aromatic molecules: a surprising case of mixed conjugation, rehybridization, and induction contributions.

Methyl-substituted, six-membered aromatic molecules are deprotonated to benzylic carbanions, which are stabilized by π conjugation. In contrast, deprotonation of 3(5)-methylpyrazole (NH protected) occurs at an endocylic CH group. Computational analyses showed that the reduction of π conjugation in substituted five-membered rings plays a major role, while the reduced bond angles, in addition to the strengthened induction of Csp(2) versus Csp(3), further favor the deprotonation of endocyclic carbon sites rather than that of the methyl group.