Search

ConspectusOne of the constant challenges of synthetic chemistry is the molecular design and synthesis of nonionic, metal-free superbases as chemically stable neutral organic compounds of moderate molecular weight, intrinsically high thermodynamic basicity, adaptable kinetic basicity, and weak or tunable nucleophilicity at their nitrogen, phosphorus, or carbon basicity centers. Such superbases can catalyze numerous reactions, ranging from C-C bond formation to cycloadditions and polymerization, to name just a few. Additional benefits of organic superbases, as opposed to their inorganic counterparts, are their solubility in organic reaction media, mild reaction conditions, and higher selectivity. Approaching such superbasic compounds remains a continuous challenge. However, recent advances in synthetic methodology and theoretical understanding have resulted in new design principles and synthetic strategies toward superbases. Our computational contributions have demonstrated that the gas-phase basicity region of 350 kcal mol-1 and even beyond is easily reachable by organosuperbases. However, despite record-high basicities, the physical limitations of many of these compounds become quickly evident. The typically large molecular weight of these molecules and their sensitivity to ordinary reaction conditions prevent them from being practical, even though their preparation is often not too difficult. Thus, obviously structural limitations with respect to molecular weight and structural complexity must be imposed on the design of new synthetically useful organic superbases, but strategies for increasing their basicity remain important.The contemporary design of novel organic superbases is illustrated by phosphazenyl phosphanes displaying gas-phase basicities (GB) above 300 kcal mol-1 but having molecular weights well below 1000 g·mol-1. This approach is based on a reconsideration of phosphorus(III) compounds, which goes along with increasing their stability in solution. Another example is the preparation of carbodiphosphoranes incorporating pyrrolidine, tetramethylguanidine, or hexamethylphosphazene as a substituent. With gas-phase proton affinities of up to 300 kcal mol-1, they are among the top nonionic carbon bases on the basicity scale. Remarkably, the high basicity of these compounds is achieved at molecular weights of around 600 g·mol-1. Another approach to achieving high basicity through the cooperative effect of multiple intramolecular hydrogen bonding, which increases the stabilization of conjugate acids, has recently been confirmed.This Account focuses on our efforts to produce superbasic molecules that embody many desirable traits, but other groups' approaches will also be discussed. We reveal the crucial structural features of superbases and place them on known basicity scales. We discuss the emerging potential and current limits of their application and give a general outlook into the future.

With the synthesis of N, N′, N″, N‴-tetrakis(3- (dimethylamino)propyl)triaminophosphazene (TDMPP, 1), we present the first phosphazene superbase with enhanced basicity through the effect of multiple intramolecular hydrogen bonding (IHB). Due to intramolecular solvation of four NH protons, the proton affinity is even higher than that of second-order phosphazene (dma)P2-tBu. X-ray structural proof, NMR titration experiments, and computational investigations provide a more detailed quantitative description of the IHB influence on the superbasicity of 1 in solid-state, solution, and the gas-phase.

In the present study, N-methyl-2, 4, 6- cycloheptatriene-1-imine (Troponimine) with (Me)2N- and MeO- substituents have been investigated theoretically to evaluate their suitability as a new neutral organic superbase. To introduce the aforementioned system, thermochemical parameters such as gas basicity and proton affinity have been calculated along with their pKBH+ values in acetonitrile. Results revealed that all studied troponimine derivatives are more basic than 1, 8- bis(dimethylamino)-naphthalene whose gas phase basicity of 237 kcal mol-1 is considered to be the borderline between ordinary bases and superbases. However, the most important finding is that some of the proposed troponeimines are much stronger bases than the well-established cyclopropenimine superbases. Origin of troponimine basicity is elucidated through NICS calculations which reveal that troponimines become aromatic upon protonation. AIM analyses revealed that the hydrogen bond could also contribute to the basicity if a suitable substituent is located on the adjacent of the imine group of the troponimine.

Dipeptidyl peptidase III (DPP III) is a zinc-dependent peptidase that cleaves dipeptides off of N-termini of its substrates. Previous studies on human DPP III reveal a reaction mechanism similar to that of thermolysin. Since the active site is conserved within the DPP III family, it is not surprising that the mechanism determined for Bacteroides thetaiotaomicron DPP III (BtDPP III) closely resembles that of hDPP III. However, the hydrogen bond network within the model differs slightly from that in the human ortholog, which results in two proposed pathways. The calculated Gibbs activation energy of 90.1 kJ mol–1 is larger than the one calculated from kinetic data for the preferred substrate Arg2-2-naphthylamide at room temperature (69 kJ mol–1), suggesting the importance of treating the whole DPP III enzyme in the calculations. This work is licensed under a Creative Commons Attribution 4.0 International License.

Utilizing dialkylamino cyclopropenimines as hydrogen bond acceptors in tri-substituted guanidines and cyclopropenimines, we computationally designed the most basic superbases possessing intramolecular hydrogen bonds (IHB-superbases) so far. The values of proton affinity in the gas phase range between 296.6 and 306 kcal mol−1, with estimated pKa values in acetonitrile between 35.5 and 39.7. The obtained PAs of five new IHB-superbases surpass the basicity of the paradigmatic P4-tBu Schwesinger phosphazene, whereas pKa values come close to that of P4-tBu. None of the designed superbases contain phosphorus, which puts them among few most basic non-phosphorus superbases desiged so far.

New organic superbases have been designed using the concept of multiple intramolecular hydrogen bonds. Substituents capable of forming strong intramolecular H-bonds were selected on the basis of the energy of stabilization that occurs upon the formation of a complex between N,N',N"-trimethylguanidine and small model molecules. The proton affinities and the corresponding pK(a) values in acetonitrile of the new superbases are examined by Density Functional Theory (DFT). It is shown that N,N',N"-substitution of guanidine with appropriate substituents results in new organic superbases with gas phase proton affinities between 286 and 293 kcal mol(-1), thus being 15 to 20 kcal mol(-1) more basic than parental superbase N,N',N"-tris[(3-dimethylamino)propyl]-guanidine (tris-DMPG), whereas estimated pK(a) values in acetonitrile range between 29.5 and 33.2.

Human dipeptidyl-peptidase III (h.DPP III) is a zinc-exopeptidase that hydrolyses dipeptides from the N-terminus of its substrates. Its mechanism of action was assumed to be similar to that of thermolysin, but was never thoroughly investigated. This study presents the first insight into the reaction mechanism of h.DPP III, determined on the model and real (hydrated enzyme with Leu-enkephalin bound in the active site) systems. The Glu451-assisted water addition on amide carbon atoms and nitrogen inversion (i.e. change of pyramidalization on the leaving nitrogen) are shown to be the rate-determining steps with the activation energies in a good agreement with the experimental results for the Leu-enkephalin hydrolysis. The energy barrier for nucleophilic attack is about 28 kJ mol-1, while barriers for the N-inversion differ as a consequence of the number of hydrogen bonds that have to be changed, which is smaller in the model active site than in the solvated enzyme. Although precisely defined geometry of the enzyme binding site puts an additional restraint on the hydrogen bonding interactions, at the same time it stimulates the forward reaction towards the final hydrolytic product. Namely, different from the model, the N-inversion is in a concerted fashion followed by favourable hydrogen bonding with Glu451 that immediately "locks" the system into the configuration where reversion to the enzyme-substrate complex is hardly achievable. Therefore we propose that the functional significance of DPP III is dual: to lower the energy barrier of the peptide hydrolysis and to suppress the reverse reaction.

It is shown by a reliable DFT method that supramolecular structures 1 and 2, constructed using pyridine as an essential building block, act as powerful neutral organic superbases in the gas phase and in acetonitrile due to cationic resonance and hydrogen bonding in the conjugate acids amplified by the NMe2 groups placed at strategic positions on the molecular backbone.

It is shown by reliable DFT B3LYP/6-311+G(2df, p)//B3LYP/6-31G* method that pyridine and s-triazine can serve as useful building blocks in tailoring neutral superbases. The former compound is used in constructing the four-fragment macrocycles substituted by a number of NMe2 substituents placed at strategic positions on the suprastructures backbone. The calculated proton affinities are within the range of 270-290 kcal mol-1, thus belonging to the upper part of the superbasicity ladder. It is shown that proton affinities of polysubstituted derivatives follow a simple additivity rule, which facilitates prediction and interpretation of the results in multiply substituted systems. The s-triazine motif is employed in forming manxane-like systems by using guanidine fragments or 1, 1-dimethylaminoethylenes, which exhibit proton affinities spread over the lower part of the superbasicity scale (256-272 kcal mol-1). The amplified basicity in both families of compounds is a consequence of the strong cationic resonance in conjugate acids supported by stabilization provided by intramolecular hydrogen bonds (IMHB). The nature of the IMHBs is examined. It is found that IMHBs in large macrocycles constructed by pyridine moieties is of a bicentric type. They are not cationic resonance supported IMHBs in the first approximation. In contrast, protonation in one of the manxane-like systems yields the IMH bonds that are stabilized by substantial cationic resonance through the hydrogen H+ bridge. Consequently, the cationic resonance supported hydrogen bonds (CRSHBs) do exist in some protonated species. The basicity of pyridine macrocycles is examined in acetonitrile. It is found that their pKa values span a range between 26-30 units meaning that they are also strong superbases in MeCN solutions compared to the threshold given by pKa(MeCN) of DMAN (18.2 units).

The MP2(fc)/6-311+G**//HF/6-31G* and B3LYP/6-311+G**//HF/6-31G* calculations show that N-[3-(dimethylamino)propyl] and N-[4-(dimethylamino)butyl] derivatives of 2,3-diamino-cycloprop-2-ene-1-imine (CPI) possess high gas phase proton affinities (PA) and pronounced basicities in acetonitrile (MeCN). Tris[N-dimethylaminopropyl(-butyl)]-CPI derivatives achieve superbasic PA and pKa values. The reason behind these remarkable features is the stability of the resulting conjugate acids. They are stabilized by aromatization of the three-membered ring accompanied by the cationic resonance between the cyclopropyl ring and amino nitrogen atoms of the side chains, and, last but not least, by the cooperative multiple intramolecular hydrogen bonding effect. The latter is particularly enhanced in tris-substituted CPIs. It was found that the N-[4-(dimethylamino)butyl] side chains contribute more to the stability of the conjugate acids than those of the corresponding compound with a propyl chain, because they undergo a somewhat larger relaxation upon protonation. The studied compounds might be helpful in building up a dense ladder of strong bases and superbases, which could contribute to the development of the chemistry of superacids and superbases. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The spatial and electronic structure of the very strong neutral organic bases bis(tetramethylguanidino)naphthalene (TMGN), 4,5-bis(tetramethylguanidino)fluorene (TMGF) and some related compounds are explored by ab initio computational methods. Their affinity towards the proton is scrutinized both in the gas phase and in solution in acetonitrile. The protonation at the most basic center (the imine nitrogen) yields asymmetric and relatively strong intramolecular hydrogen bonds (IHB). It is found that the angular strain effect and steric repulsion practically vanish in TMGN which implies that its high absolute proton affinity (APA) has its origin in the inherent basicity of the guanidine fragment and a relatively strong IHB in [TMGN]H(+). The nonbonded repulsions in TMGF are higher than in TMGN, which in conjunction with a slightly stronger IHB in the corresponding conjugate acid makes it more basic: APA(TMGF)>APA(TMGN). An interesting new phenomenon is observed in both TMGN and TMGF: the proton triggers the resonance stabilization not only in the directly bonded guanidine moiety, but also in the other guanidine fragment which is more distant from the proton, albeit in a less pronounced manner. The latter feature is termed a partial protonation. This supports the hydrogen bonding and contributes to the IHB stabilization. Convincing evidence is presented that the solvent effect in acetonitrile is determined by two antagonistic factors: 1) the intrinsic (gas phase) proton affinity and 2) the size effect which is given by the ratio between the positive charge in molecular cation (conjugate acid) and the magnitude of the molecular surface. The resulting pK(a) values are given by an interplay of these factors.

Multiple aminopropyl substitutions of the initial N,N′,N″-trimethylguanidine lead to high intrinsic absolute proton affinities (APA) and basicities culminating in APA = 268.4 kcal mol−1 (1 kcal = 4.184 kJ) in N,N′,N″-tris(3-aminopropyl)guanidine (9). The reason behind a high proton affinity is identified as a strong cationic resonance in the central guanidine moiety and the strength of the intramolecular hydrogen bonding (IMHB), which is enhanced upon protonation. A cooperative IMHB effect in 9 and 9H+ realized by three N(sp3)H···N(sp3) H-bridges is estimated to be as high as 14.7 and 33.0 kcal mol−1, respectively. It follows that the IMHB effect contributes 18.3 kcal mol−1 to the absolute proton affinity of 9, which is a respectable amount. The basicity of 9 in acetonitrile is estimated to be very high, as evidenced by the corresponding pKa = 28.8. A derivative of 9, N,N′,N″-tris(3-dimethylaminopropyl)guani-dine (10), assumes an even higher superbasic proton affinity of 275 kcal mol−1 due to an additional relaxation effect caused by the methyl groups. The corresponding pKa(MeCN) = 29.4. Copyright © 2002 John Wiley & Sons, Ltd.

The role of intramolecular hydrogen bonding (IMHB) in determining the proton affinities and basicities of some bis(tetramethylguanidine)systems was examined. For this purpose a series of molecular backbone moieties serving as carriers of the bis(tetramethylguanidine)crowns were explored. It was found that the best backbones are provided by phenanthrene and 9,10-dihidrophenanthrene, giving rise to proton affinities as large as 268.2 and 266.8 kcal mol1−, respectively. The corresponding pKa values in acetonitrile are 29.0 and 28.8, implying that these two compounds [6(bs)and 5(bs)] are candidates for powerful superbases. Their intramolecular hydrogen bond strengths are ≈19 kcal mol1−, which result inter alia from the partial protonation of the vis-a-vis guanidine group.

Utilizing several different trialkylarsine oxides and substituted pyridine N-oxides as a hydrogen bond acceptors in tri-substituted guanidines we designed several very basic superbases possessing intramo-lecular hydrogen bonds (IHB-superbases), with proton affinity in the gas phase that comes very close to that of paradigmatic P4-tBu Schwesinger superbase and with pKa in acetonitrile up to 36 units.

The absolute proton affinities (APA) of 20 α-amino acids, as obtained by the MP2(fc)/6-311+G∗∗//HF/6-31G∗ + ZPVE(HF/6-31G∗) and the scaled Hartree–Fock (HFsc) models, are presented. It is shown that the α-NH2 group is protonated in all but four cases: lysine (K), proline (P), histidine (H), and arginine (R). There is a good overall agreement with experimental data measured by the kinetic method. However, there are some notable exceptions such as glutamine (Q) and lysine (K), where strong hydrogen bonds in the protonated forms occur. It is suggested that the present results and theoretical models employed could be useful for resolving such experimental ambiguities. Furthermore, it appears that the HFsc model provides an efficient tool for elucidating APAs of artificial α-AAs, derivatives of natural α-AAs and their oligomers.

The problem of the intramolecular proton transfer isomerism in arginine, leading to conventional neutral and zwitterionic forms of this compound, is addressed by high level theoretical models. It is shown that arginine has two neutral and two zwitterionic isomers implying that there exist two additional unconventional isomers, which have not been identified so far. It appears also that the most stable neutral isomer is energetically more favourable than both zwitterions, which implies that the former should be preferred in the gas phase. Examination of atomic charges obtained by the electron density partitioning techniques reveals that the charge distributions of neutral and zwitterionic isomers are not as widely different as expected. This finding is counterintuitive, since it contradicts the classical notion of chemical bonding and a customary picture of zwitterions involving two local complementary fragments possessing unit charges of opposite sign. The true distribution of the electron density is more uniform and quite similar to that of the neutral form. The proton affinity of arginine is estimated to be 249 kcal mol–1. Hence, it follows that arginine is a very basic compound although it belongs to a family of 20 fundamental α-amino acids. A very high proton affinity is interpreted in terms of the resonance effect spurred by protonation in the guanidine moiety and by a strong hydrogen bonding taking place in the protonated form.

The gas phase basicities and pKa values in acetonitrile of azacalix[3](2,6)pyridine and its derivatives are determined by the B3LYP DFT method. It is found that all compounds of this series are neutral organic superbases. The proton attacks the inner pyridine N(sp2) atom, thus forming a bifurcated intramolecular hydrogen bond. The most powerful superbase is provided by the hexakis(dimethylamino) derivative of the title compound. Its gas phase proton affinity is 296.6 kcal mol-1, its basicity is 291.3 kcal mol-1, and its pKa(MeCN) is 30.9 units. [structure: see text]

It is shown that a combination of Schwesinger's phosphazene base concept and the idea of the disubstituted 1,8-naphthalene spacer, first introduced by Alder in paradigmatic 1,8-bis(dimethylamino)naphthalene (DMAN), yields a new superbase, HMPN, which represents the up to date most basic representative of this class of "proton sponges", as evidenced by the theoretically estimated proton affinity PA = 274 kcal/mol and the measured pK(BH+) (MeCN) 29.9 +/- 0.2. HMPN is by nearly 12 orders of magnitude more basic than Alder's classical 1,8-bis(dimethylamino)naphthalene (DMAN). The title compound, HMPN, is prepared and fully characterized. The spatial structure of HMPN and its conjugate acid is determined by X-ray technique and theoretical DFT calculations. It is found that monoprotonated HMPN has an unsymmetrical intramolecular hydrogen bridge (IHB). This cooperative proton chelating effect renders the bisphosphazene more basic than Schwesinger's set of "monodentate" P1 phosphazene bases. The density functional calculations are in good accordance with the experimental results, providing some complementary information. They conclusively show that the high basicity of HMPN is a consequence of the high energy content of the base in its initial neutral state and the intramolecular hydrogen bonding in the resulting conjugate acid with contributions to proton affinity of 14.1 and 9.5 kcal/mol, respectively.

The synthesis of novel N, N', N'' tris(3 dimethylaminopropyl)-guanidine 1 is described and the X-ray structure of its hexafluorophosphate salt measured (1H· PF6). The hydrogen bonding in protonated 1 and in 1H· PF6 is also discussed.

Gas-phase H/D exchange experiments with CD3OD and D2O and quantum chemical ab initio G3(MP2) calculations were carried out on protonated histidine and protonated histidine methyl ester in order to elucidate their bonding and structure. The H/D exchange experiments show that both ions have three equivalent fast hydrogens and one appreciably slower exchangeable hydrogen assigned to the protonated amino group participating in a strong intramolecular hydrogen bond (IHB) with the nearest N(sp2) nitrogen of the imidazole fragment and to the distal ring NH-group, respectively. It is taken for granted that the proton exchange in the IHB is much faster than the H/D exchange. Unlike in other protonated amino acids (glycine, proline, phenylalanine, tyrosine, and tryptophan) studied earlier, the exchange rate of the carboxyl group in protonated histidine is slower than that of the amino group. The most stable conformers and the enthalpies of neutral and protonated histidine and its methyl ester are calculated at the G3(MP2) level of theory. It is shown that strong intramolecular hydrogen bonding between the amino group and the imidazole ring nitrogen sites is responsible for the stability and specific properties of the protonated histidine. It is found that the proton fluctuates between the amino and imidazole groups in the protonated form across an almost vanishing barrier. Proton affinity (PA) of histidine calculated by the G3(MP2) method is 233.2 and 232.4 kcal mol(-1) for protonation at the imidazole ring and at the amino group nitrogens, respectively, which is about 3-5 kcal mol(-1) lower than the reported experimental value.

We performed a comparative spectroscopic FTIR and computational study of the vibrational OH stretching frequencies in liquid ethanol–ethanol (I) and liquid ethanol–N-methylimidazole dimers (II). The latter system mimics the hydrogen bond formation between serine and histidine residues, which is the incipient step in the enzymatic activity of the catalytic triads. Complex (I) was studied as a reference system. The infrared spectra revealed the presence of the OH fundamental stretching transitions at 3339 and 3271 cm � 1 for complexes (I) and (II), respectively. This red shift of 68 cm � 1 indicates that the hydrogen bond between ethanol and N-methylimidazole exists and it is favoured over the one occurring in ethanol dimers. It is shown that vibrations exhibit anharmonicity.

1,8-Bis(dimethylethyleneguanidino)naphthalene (DMEGN), the second example of a peralkyl guanidine “proton sponge” based on the 1,8-naphthalene backbone, was prepared and fully characterized. The crystal structure analysis of monoprotonated DMEGN reveals an unsymmetrical intramolecular hydrogen bridge. A decrease in the basicity with respect to the noncyclic parent 1,8-bis(tetramethylguanidino)naphthalene was found. Nevertheless, a new proton sponge provides a new crossbar in the ladder of highly basic neutral organic compounds. A detailed theoretical study of DMEGN and related cyclic guanidines explains this surprising experimental result. Homodesmotic reactions reveal that the intramolecular hydrogen bond contributes effectively 10 kcal/mol to proton affinity of DMEGN.