Cooperativity and proton transfer in hydrogen-bonded triads.

Ab initio MP2/6-311+G(3df,2pd) and MP2/aug-cc-pVTZ calculations have been carried out to investigate the structures and properties of AHXHYH(3) (A=F, Cl; X=F, Cl; Y=N, P) hydrogen-bonded complexes. Significant cooperative effects are observed in the XHYH3 dyads in the triads due to the presence of the polar near-neighbor AH. These effects are greater when the polar partner is HF, which is a better proton donor than HCl. Structural changes, red shifts of proton-donor stretching frequencies, nonadditive interaction energies, and electron density redistributions unambiguously demonstrate that the X--HY hydrogen bond (HB) is stronger in the triads than in the corresponding dyads, while the X--H bond of the proton donor becomes weaker. Even more pronounced cooperative effects are observed in the AHXH dyads due to the presence of the YH3 partner. These effects are weaker in complexes having PH3 rather than NH3 as the proton acceptor, since NH3 is a stronger base. Cooperativity also enhances the proton-donating ability of the YH3 moiety, with the result that all complexes except FHFHPH3 are cyclic. Cooperativity, together with the ease of breaking the Cl--H bond in ClHClHNH3 and FHClHNH3, leads to proton transfer (PT), so that these two complexes are better described as approaching hydrogen-bonded ClHCl- x +HNH3 and FHCl- x +HNH3 ion pairs.     

New di-(beta-chloroethyl)-alpha-amides on N-(meta-acylamino-benzoyl)- D,L-aminoacid supports with antitumoral activity

In order to obtain new compounds with antitumoural action the N-(meta-acylaminobenzoyl)-alpha-acylaminobenzoyl)-alpha-aminoacids 4-9 were prepared. These compounds were subsequently converted into the corresponding Delta(2)-oxazolin-5-ones 10-15, which in turn were submitted to a ring opening reaction with di-(beta-chloroethyl)amine to afford the peptide supported N-mustards 16-21, which showed low toxicity and cytostatic activity similar to that of sarcolisine against the Ehrlich ascite and Walker 253 carcinosarcoma.     

Why Are Selenouracils as Basic as but Stronger Acids than Uracil in the Gas Phase?

The gas‐phase basicity and acidity of 2‐selenouracil ( 2SU ), 4‐selenouracil ( 4SU ), and 2,4‐diselenouracil ( 24SU ) have been calculated at the B3LYP/6‐311+G(3df,2p) level of theory. Our results showed that all these compounds behave as bases of moderate strength in the gas phase. As was found for uracil and for the thiouracil analogues, the most basic site is the heteroatom at position 4, and only for 2SU is there a certain ambiguity in assigning the basic site. More importantly, with the only exception of 2SU , selenouracils are as basic as or slightly less basic than uracil, because the replacement of the oxygen atom at position 2 by a selenium atom leads to an increase of the electron delocalization inside the six‐membered ring, which decreases the intrinsic basicity of the heteroatom at position 4. As already reported for uracil and thiouracils, for selenouracils N1 is the most acidic site. However, selenouracils are predicted to be stronger acids than uracil. This acidity enhancement is essentially due to a specific stabilization of the anion when O is replaced by Se. Two factors are responsible for this stabilization: a significant aromatization of the ring upon deprotonation and a better dispersion of the excess electron density when the system contains third‐row atoms.     

Resonance-assisted hydrogen bonds: a critical examination. Structure and stability of the enols of beta-diketones and beta-enaminones

The characteristics of the intramolecular hydrogen bond (IMHB) for a series of 40 different enols of beta-diketones and their nitrogen counterparts have been systematically analyzed at the B3LYP/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) level of theory. In some cases, two tautomers may exist which are interconnected by a hydrogen shift through the IMHB. In tautomer a the HB donor group (YH) is attached to the six-membered ring, while in tautomer b the HB acceptor (X) is the one that is attached to the six-membered ring. We found that changing an O to a N favors the a tautomer when the atom is endo and the contrary when it is exo, while the presence of a double bond favors the a tautomers. As expected, the OH group behaves as a better HB donor than the NH2 group and the C=NH group as a better HB acceptor than the C=O group, although the first effect clearly dominates. Accordingly, the expected IMHB strength follows the [donor, acceptor] trend: [OH, C=NH] > [OH, C=O] > [NH2, C=NH] > [NH2, C=O]. For all those compounds in which the functionality exhibiting the IMHB is unsaturated (I-type), the IMHB is much stronger than in their saturated counterparts (II-type). However, when the systems of the II-type subset, which are saturated, are constrained to have the HB donor and the HB acceptor lying in the same plane and at the same distance as in the corresponding unsaturated analogue, the IMHB is of similar or even larger strength. Hence, we conclude that, at least for this series of unsaturated compounds, the resonance-assisted hydrogen bond effect is not the primary reason behind the strength of their IMHBs, which is simply a consequence of the structure of the sigma-skeleton of the system that keeps the HB donor and the HB acceptor coplanar and closer to each other.     

Effect of Ni(ii), Cu(ii) and Zn(ii) association on the keto-enol tautomerism of thymine in the gas phase

The effect of Ni(II), Cu(II) and Zn(II) association on the diketo/keto-enol tautomerism of thymine has been investigated through the use of B3LYP density functional theory calculations. Final energies were obtained at the B3LYP/6-311+G(2df,2p)//B3LYP/6-311+G(d,p) level of theory. Ni(II) and Cu(II) lead to an oxidation of thymine which for Zn(ii) is only partial and catalyze the tautomerization process, this catalytic effect being much larger for Ni(2+) and Zn(2+) than for Cu(2+). One of the most significant consequences of the oxidation of the base is that the calculated BDE's are primarily dictated by the value of the second ionization potential of the metal, and therefore follow the sequence Cu(2+) > Ni(2+) > Zn(2+). Also importantly, metal dication association leads to a stabilization of the keto-enol tautomer, which becomes the most stable form upon interaction with Ni(2+) and Zn(2+). This stabilization enhancement is the consequence of three concomitant factors, namely, (i) a stronger interaction of the metal cation with the carbonyl oxygen, (ii) the interaction of the metal with the dehydrogenated ring nitrogen, (iii) an aromatization of the six-membered ring.     

Acylated manoyl oxide diterpenes of Stemodia trifoliata

Two new labdane diterpenes, 6α‐malonyloxy‐ethyl ester manoyl oxide and bis‐6α‐dioxymanoylmalonate, together with the known 6α‐hydroxymanoyl oxide, 6α‐malonyloxymaloyl oxide and betulinic acid were isolated from leaves of Stemodia trifoliata. Their structures were elucidated by spectroscopic studies (IR and HR‐ESI‐MS), including an extensive NMR (COSY, HSQC, HMBC and NOESY) analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Gas-phase protonation and deprotonation of acrylonitrile derivatives N[triple chemical bond]C--CH==CH--X (X=CH(3), NH(2), PH(2), SiH(3))

A combined experimental and theoretical study on the gas-phase basicity and acidity of a series of cyanovinyl derivatives is presented. The gas-phase basicities and acidities of (N[triple chemical bond]C--CH==CH--X, X=CH(3), NH(2)) were obtained by means of Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry techniques. The corresponding calculated values were obtained at the G3B3 level of theory. The effects of exchanging CH(3) for SiH(3), and NH(2) for PH(2), were analyzed at the same level of theory. For the neutral molecules, the Z isomer is always the dominant species under standard gas-phase conditions at 298 K. The loss of the proton from the substituent X was found systematically to be much more favorable than deprotonation of the HC==CH linking group. The corresponding isomeric E ion is much more stable than the Z ion, so that only the former should be found in the gas phase. The most significant structural changes upon deprotonation occur for the methyl and amino derivatives because, in both cases, deprotonation of X leads to a significant charge delocalization in the corresponding anion. Protonation takes place systematically at the cyano group, whereby the isomeric E ion is again more stable than the Z ion. Push-pull effects explain the preference of aminoacrylonitrile to be protonated at the cyano group, which also explains the high basicity of this derivative relative to other members of the analyzed series that present rather similar gas-phase basicities, GB approximately 780 kJ mol(-1), indicating that the different nature of the substituents has only a weak effect on the intrinsic basicity of the cyano group. The cyanovinyl derivatives have a significantly stronger gas-phase acidity than that of the corresponding vinyl compounds CH(2)==CH--X. This acidity-strengthening effect of the cyano group is attributed to the greater stabilization of the anion with respect to the corresponding neutral compound.     

The NICS (Nucleus-Independent Chemical Shift) as a probe of the relative stability of β-chalcogenovinylaldehydes stabilized through intramolecular chalcogen–chalcogen interactions

Density functional calculations, at the B3LYP/6-311+G(3df,2p) level, have been carried out for the complete series of β-chalcogenovinylaldehydes, CH(X)–CHCH–YH (X, Y=O, S, Se, Te), to estimate the strength of H–XY or XY–H intramolecular chalcogen–chalcogen interactions, through the use of appropriate homodesmotic reactions. For the same set of compounds the value of the nucleus-independent chemical shift (NICS), on points 1 Å above the corresponding ring critical point, has been obtained at the B3LYP/6-311+G(3df,2p) level. For non-stabilizing chalcogen–chalcogen interactions the NICS value is positive, while the opposite is found when the interaction is stabilizing. In general, there is a good linear correlation between both magnitudes and therefore, we can conclude that NICS value is a reliable probe of the strength of intramolecular chalcogen–chalcogen interactions in this set of compounds.     

Resonance‐Assisted Intramolecular Chalcogen–Chalcogen Interactions?

High-level B3LYP/6-311+G(3df,2p) density functional calculations have been carried out for a series of saturated chalcogenoaldehydes: CH(X)-CH(2)-CH(2)YH (X, Y=O, S, Se, Te). Our results indicate that in CH(X)-CH(2)-CH(2)YH (X=Y=O, S, Se) the X-H...X intramolecular hydrogen bond (IHB) competes in strength with the X...XH chalcogen-chalcogen interaction, while the opposite is found for the corresponding tellurium-containing analogues. For those derivatives in which X does not equal Y, X being the more electronegative atom, the situation is more complicated due to the existence of two non-equivalent X-H and Y-H tautomers. The Y-H tautomer is found to be lower in energy than the X-H tautomer, independently of the nature of X and Y. For X=O, S, Se and Y=S, Se the most stable conformer b is the one exhibiting a Y-H...X IHB. Conversely when Y=Te, the chelated conformer d, stabilized through a X...YH chalcogen-chalcogen interaction is the global minimum of the potential energy surface. Systematically the IHB and the chalcogen-chalcogen interactions observed for saturated compounds are much weaker than those found for their unsaturated analogues. This result implies that the nonbonding interactions involving chalcogen atoms, mainly Se and Te, are not always strongly stabilizing. This conclusion is in agreement with the fact that intermolecular interactions between Se and Te containing systems with bases bearing dative groups are very weak. We have also shown that these interactions are enhanced for unsaturated compounds, through an increase of the charge delocalization within the system, in a mechanism rather similar to the so call Resonance Assisted Hydrogen Bonds (RAHB). The chalcogen-chalcogen interactions will be also large, due to the enhancement of the X-->Y dative bond, if the molecular environment forces the interacting atoms X and Y to be close each other.     

Unimolecular reactivity of uracil-Cu(2+) complexes in the gas phase.

The gas-phase interaction of copper(II) ions with uracil are studied by means of mass spectrometry and B3LYP/6-311+G(2df,2p)//B3LYP/6-31G(d) calculations. Positive-ion electrospray spectra show that the reaction of uracil with copper(II) gives rise to singly charged species, whereby the [Cu(uracil--H)](+) complex is the most intense ion in the spectra at low concentration. Mass spectrometry/mass spectrometry (MS/MS) experiments show that the loss of HNCO and NCO are the dominant fragmentation processes, accompanied by a minor loss of CO. A systematic study of the spectra obtained with different labeled species, namely, 2-(13)C- (m/z 175), 2-(13)C,1,3-(15)N(2)- (m/z 177) and 3-(15)N-uracil (m/z 175), concludes unambiguously that both the loss of HNCO and NCO involve exclusively C2 and N3, whereas only C4 is involved in the loss of CO. Suitable mechanisms for these fragmentation processes are proposed through a theoretical survey of the corresponding potential energy surface. In these mechanisms, pi complexes, which lie high in energy with respect to the global minimum, play a significant role in the loss of NCO; this explains why both products, HNCO and NCO involve the same atoms of the ring.