Unveiling the Shape of Aspirin in the Gas Phase

Cabezas, Carlos; Alonso, José L.; López, Juan C.; Mata, Santiago

doi:10.1002/ange.201106621

Cited by 12 publications

(16 citation statements)

References 38 publications

(34 reference statements)

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“…Other medicinal implications of n→π* interactions have become apparent. For example, an n→π* interaction in aspirin (10) was revealed through both crystallographic 24 and spectroscopic 86 investigations. Donation of electron density from the anionic carboxylate into the ester carbonyl group is predicted to shield and disperse negative charge on the molecule and thereby to improve its entry into cells.…”

Section: Drugsmentioning

confidence: 99%

The n→π* Interaction

2017

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ConspectusThe carbonyl group holds a prominent position in chemistry and biology not only because it allows diverse transformations but also because it supports key intermolecular interactions, including hydrogen bonding. More recently, carbonyl groups have been found to interact with a variety of nucleophiles, including other carbonyl groups, in what we have termed an n→π* interaction. In an n→π* interaction, a nucleophile donates lone-pair (n) electron density into the empty π* orbital of a nearby carbonyl group. Mixing of these orbitals releases energy, resulting in an attractive interaction. Hints of such interactions were evident in small-molecule crystal structures as early as the 1970s, but not until 2001 was the role of such interactions articulated clearly.These non-covalent interactions were first discovered during investigations into the thermostability of the proline-rich protein collagen, which achieves a robust structure despite a relatively low potential for hydrogen bonding. It was found that by modulating the distance between two carbonyl groups in the peptide backbone, one could alter the conformational preferences of a peptide bond to proline. Specifically, only the trans conformation of a peptide bond to proline allows for an attractive interaction with an adjacent carbonyl group, so when one increases the proximity of the two carbonyl groups, one enhances their interaction and promotes the trans conformation of the peptide bond, which increases the thermostability of collagen.More recently, attention has been paid to the nature of these interactions. Some have argued that rather than resulting from electron donation, carbonyl interactions are a particular example of dipolar interactions that are well-approximated by classical mechanics. However, experimental evidence has demonstrated otherwise. Numerous examples now exist where an increase in the dipole moment of a carbonyl group decreases the strength of its interactions with other carbonyl groups, demonstrating unequivocally that a dipolar mechanism is insufficient to describe these interactions. Rather, these interactions have important quantum-mechanical character that can be evaluated through careful experimental analysis and judicious use of computation.Although individual n→π* interactions are relatively weak (∼0.3–0.7 kcal/mol), the ubiquity of carbonyl groups across chemistry and biology gives the n→π* interaction broad impact. In particular, the n→π* interaction is likely to play an important role in dictating protein structure. Indeed, bioinformatics analysis suggests that approximately one-third of residues in folded proteins satisfy the geometric requirements to engage in an n→π* interaction, which is likely to be of particular importance for the α-helix. Other carbonyl-dense polymeric materials like polyesters and peptoids are also influenced by n→π* interactions, as are a variety of small molecules, some with particular medicinal importance. Research will continue to identify molecules whose conformation and activity are affect...

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Section: Drugsmentioning

confidence: 99%

The n→π* Interaction

2017

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“…1 A) 34 . First discussed in early 1970, the n → π * interaction has attracted significant attention in recent years and it is hypothesized to impart substantial structural stability to proteins 35 – 38 and molecules 39 – 42 , as well as define reactivity 40 , regulate isomerisation 34 and energy barriers 43 , and promote charge transfer 44 . Nevertheless, the actual dynamical implications at finite temperature of such interaction have not been explicitly studied.…”

Section: Resultsmentioning

confidence: 99%

“…2 a) and two other local minima (Fig. 2 b, c), thereby defining their energetic ordering 39 , 40 . Figure 2 shows the configuration space sampling obtained from classical MD and PIMD simulations at room temperature, where the dynamical implications of the NQE on aspirin’s behavior are evident: NQE constrains the dynamics of the molecule to the global minimum in contrast to the results from classical MD.…”

Section: Resultsmentioning

confidence: 99%

Dynamical strengthening of covalent and non-covalent molecular interactions by nuclear quantum effects at finite temperature

et al. 2021

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Nuclear quantum effects (NQE) tend to generate delocalized molecular dynamics due to the inclusion of the zero point energy and its coupling with the anharmonicities in interatomic interactions. Here, we present evidence that NQE often enhance electronic interactions and, in turn, can result in dynamical molecular stabilization at finite temperature. The underlying physical mechanism promoted by NQE depends on the particular interaction under consideration. First, the effective reduction of interatomic distances between functional groups within a molecule can enhance the n → π* interaction by increasing the overlap between molecular orbitals or by strengthening electrostatic interactions between neighboring charge densities. Second, NQE can localize methyl rotors by temporarily changing molecular bond orders and leading to the emergence of localized transient rotor states. Third, for noncovalent van der Waals interactions the strengthening comes from the increase of the polarizability given the expanded average interatomic distances induced by NQE. The implications of these boosted interactions include counterintuitive hydroxyl–hydroxyl bonding, hindered methyl rotor dynamics, and molecular stiffening which generates smoother free-energy surfaces. Our findings yield new insights into the versatile role of nuclear quantum fluctuations in molecules and materials.

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“…A number of powerful strategies have been found, which use a combination of laser ablation for transferring intact molecules into the gas phase, rapid cooling in a free jet expansion to stabilize their conformers, and highly selective Fourier‐transform microwave spectroscopy to probe the most stable conformers (this method is known as LA‐MB‐FTMW) 12. Structural studies of amino acids,13 nucleic acid bases,14 neurotransmitters,15 drugs (like aspirin),16 and sugars such as glucose17 benefit from this LA‐MB‐FTMW technique 12. Recently, the microwave spectra of ribose18 and fructose19a have been characterized using a UV ultrafast laser ablation source with a Balle–Flygare FTMW spectrometer.…”

Section: Spectroscopic Parameters and Relative Energies For The α Andmentioning

confidence: 99%

Six Pyranoside Forms of Free 2‐Deoxy‐D‐ribose

et al. 2013

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A clear picture of the conformations of isolated 2‐deoxy‐D‐ribose was obtained using chirped pulse and Balle–Flygare Fourier‐transform microwave spectrometers, both coupled with laser ablation sources. Two conformers of α‐D‐deoxyribopyranose and four of β‐D‐deoxyribopyranose were found on the basis of the spectroscopic rotational parameters and ab initio predictions. The substitution and effective structures of the most abundant conformer have been determined.

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Unveiling the Shape of Aspirin in the Gas Phase

Cited by 12 publications

References 38 publications

The n→π* Interaction

The n→π* Interaction

Dynamical strengthening of covalent and non-covalent molecular interactions by nuclear quantum effects at finite temperature

Six Pyranoside Forms of Free 2‐Deoxy‐D‐ribose

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