Talk:Stacking (chemistry)

merge notice: this article definition indentical to that of Stacking (chemistry) V8rik 21:44, 4 June 2006 (UTC)

This article is badly written, filled with factual and grammatical errors, I will hopefully return in a few days to tidy it up

Stacking and pi-pi

I don't have free full-text access to this article at home : Angew Chem Int Ed Engl. 2008;47(18):3430-4. , but it seems to suggest that the pi-pi interaction description here is inaccurate. The arguments make sense to me (that Coulombic attraction between CH and pi are more responsible). Word is that the author quotes wikipedia as a source of the disinformation. It would be nice if people who saw litter were more inclined to pick it up than complain about it, but that's probably asking too much, especially if the author can use it to make their paper more noteworthy. I'll see if I have the free-text to this via work, and if so consider fixing it after reading it. As I've got the memory of a goldfish, I will probably forget, hence this note. 81.187.202.205 (talk) 22:52, 23 July 2009 (UTC)

Okay, I've had a look at the citation above, it looks good and the consequence is essentially that this whole article is screwed. I'll sort it out during my vacation, at least to the extent that it's not explicitly rubbish. According to the article, well supported by modelling in my judgement, much of stacking effect comes from Van De Waals interactions as is evidenced, for example, by similar energies from stacking cyclohexane and benzene. pi-pi interactions it seems can contribute to stacking, but only in certain (non-typical) circumstances. For example, it's umlikely to be a major contributor to the stacking effect in nucleobase (biological) circumstances. This is not yet reflected in most of the secondary literature. Obviously, there shouldn't be excessive weight to this one piece, but we need to explicitly unconfuse stacking from pi-pi and mention the two approaches ("orthodoxy" vs "recent research suggests"). This would have been a whole lot easier with Open Access, grumble grumble, Wiley, grumble grumble. 131.111.21.21 (talk) 13:30, 24 July 2009 (UTC)

Started rewrite by adding initial section. Haven't got to rewriting rest of article yet, just put in an attention of experts box. 81.187.202.205 (talk) 02:38, 25 July 2009 (UTC)

This pi-pi disinformation has been repeated in umpteen biochemistry textbooks over the yearsbut constant repetition does not make it true. The electrostatic basis of stacking is discussed at length in the text "Principles of Nucleic Acids" by Wolfram Saenger, Springer 1984 ISBN0387907629;ISBN0387907610 (pbk.) I no longer have my copy so I can't quote pages.96.54.53.165 (talk) 00:51, 22 December 2009 (UTC)

Has this article been abandoned? I just stumbled upon this page, and it drew my attention that the authors were going to re-write the article (a year ago?). For whoever continues to work on this article, please be careful in adapting the article to a single source (or only a few sources). For example, based on Stefan Grimme's 2008 article, the article says "Electrostatic forces actually considerably weaken this effect in aromatics" and "Therefore DNA nucleobases (having one or two rings) probably do not significantly stabilise DNA's stacked structure as a result of their aromaticity" The article you cited, though, is limited to non-charged aromatic arenes (where charges are small), and it also used "classical electrostatics" in the energy decomposition, which I believe means it treated each atom in the molecule as a point charge (so quadrupoles were omitted). Figure 2 shows a ~3-4 kcal/mol improvement in interaction energy with only 3 rings (just like nucleic acid base pairs). The article by Grimme is a good article in a very reputable journal, but the conclusion is that the "pi-stacking effect" is caused by "nonlocal electron correlations between the pi electrons." Anyway, I wanted to pitch in a word of encouragement that the article isn't "screwed." It just needs a few more references to round out the perspective. Hopefully someone will have time to pick this back up soon. 11:53, 11 June 2010 (jf) —Preceding unsigned comment added by Phaethonfire (talk • contribs)

There are definitely some problems with this article. I recently looked at the latest literature on this, and it is certain there is something special about stacking pi systems together. Here are some slides on what I figured out. Eugene Kwan (talk) 03:49, 22 November 2010 (UTC)

You cannot change an entire article because of one reference from one investigator -- it is a biased vantage point. Furthermore, there is zero experimental evidence for the conjecture that pi-pi are not critical forces in DNA base stacking. In other words, do an experiment in which the nucleotides are altered to have less aromaticity and get back to us on that. In any case, the haphazard editing here is kind of crazy. To re-write the topmost paragraph around a single source is reckless imho. I also find it hard to believe that there is a sudden shift energetically from a VDW type interaction to a pi-pi in larger ring systems. Is the author saying this is some sort of discontinuous function and pi-pi only suddenly occurs in larger ring systems. Sounds a little unbelievable that such a complex system is purely not using pi-pi aromatic interactions. At best the writing needs improvement to expand upon the nuances. I imagine the original article more artfully danced around this issue that was presented here. —Preceding unsigned comment added by 128.32.166.159 (talk) 23:53, 25 January 2011 (UTC)

UV absorbance

UV absorbance by the aromatic rings in DNA is suppressed due to stacking. (Compare UV absorbance of denatured DNA versus dimerised DNA.) Would Van der Waals forces suppress this? Or pi-pi interactions? 76.120.195.172 (talk) 06:44, 7 December 2010 (UTC)

More Comments

Impressions: The article is reasonably organized, but is lacking in a significant number of details and diagrams.

Suggestions:

- How about some plots of preferred orientations and distances in the PDB? Calculations? Figures for high-level geometries of stacked dimers?

- A figure would go a long way towards explaining the Houk/Wheeler, Hunter/Sanders, Sherill, etc. models. Schemes for the torsion balances and other examples you mention would also be useful.

- I like Grimme's work. That should also get a scheme. Maybe you could comment on which computational methods are appropriate for studying these interactions.

- What are the implications of the pi-stacking phenomenon, both for chemistry and biology? I think that at least in catalysis, it's much more complicated than one would like. Rather than having one stacking interaction that is clearly discernible and responsible for selectivity, it is but one of many factors. Are there specific reactions in which pi stacking is implicated? How important is it for protein folding? Ligand-receptor interactions?

- Some comments regarding the energetics of the interaction would be useful. Is having more "pi-surface" cooperative in any way? If it is a purely dispersive interaction, is it likely to increase in the transition state? At least for cation-pi interactions, that seems likely. Here, it's not so clear.

Eugene Kwan (talk) 22:05, 24 October 2011 (UTC)

A minor but important change. Added SI units (kJ) keeping the older units in parentheses (multiplied simply by 4 since the original values were only approximate). However, I feel strongly that SI units must be used as the primary. — Preceding unsigned comment added by 109.148.69.36 (talk) 09:18, 8 May 2012 (UTC)

I have to disagree. kcal are standard. kJ may be insisted on in rule books, but generally nobody uses them in this context. Went to a talk by Grimme last week, and he used them extensively. Eugene Kwan (talk) 10:37, 8 May 2012 (UTC)

Not where I am .... And most certainly not in major journals. For instance the NEJM insists that SI units be used for all clinical chemistry measurements. All major text books use SI units - my very elder copy of Lehninger (Second edition) uses Joules as does my copy of Metzler. The use of kcal outside the US is virtually unheard of (and remember wiki is international). — Preceding unsigned comment added by 31.52.122.223 (talk) 19:22, 10 May 2012 (UTC)

Isn't kcal more common in computational chemistry? --Ben (talk) 20:26, 10 May 2012 (UTC)

No... hartrees are more common ;)

Kilocalories and kilojoules are both used for describing thermochemistry (computationally or experimentally). Perhaps kcal is favored in the US, but I won't go so far as to say that it predominates. It is closer to picometers versus angstroms, than a case of milliliters versus cubic centimeters. In any case, a calorie is still an SI-derived unit. I personally find kcal convenient, because the bond dissociation energies tend to be around 100 kcal/mol.

Anyway, kcal is no more standard than kJ is. If you are reading this article, you probably will know the conversion anyway. As long as we stay consistent, we'll be fine. --Rifleman 82 (talk) 20:56, 10 May 2012 (UTC)

η⁶-coordinated moiety upon benzene (cyclopentane on benzene?)

According to the article, "The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger."

generic metallocene

Would the linked-title to this talk-section I added above constitute this kind of pi-stacking: i.e. transition metal chelate eta-six co-ordination? (cf. so-named, systematic S. Singh # 21b^d) 66.96.79.217 (talk) 01:50, 21 April 2016 (UTC)

As far as I can tell from that article and your question (which could be clearer) the benzene and cyclopentadienyl in this cocaine analog are practically on opposite sides of the molecule (I'll admit I'm slightly unclear on what they mean about the solid cone angles). So far as I can tell, your question is almost the same as asking whether a generic metallocene is a case of pi stacking... but I could be wrong. Now you can have stacked metallocenes, but I think what they usually have in mind is something like this with the two aromatic rings together. When they're on opposite sides of a metal, they may be interacting somehow via the multilobed orbitals on the metal, but I don't think that counts as stacking. I'm not that well informed in these things, so if you want a better answer, go to WP:Reference desk/Science - but if you're asking whether you should add that cocaine analog as an illustration of stacking for this article, I'm just barely confident enough to vote no. Wnt (talk) 12:44, 21 April 2016 (UTC)

Rethinking the term “pi-stacking”

I'm going to leave this citation here. There is a lot of misinformation online and I would hope that Wikipedia might be a means to get through that, even in scientific circles. Fix this page please!

References

Nonetheless, the term pi-stacking has been widely adopted in scientific literature and remains in use. I see no reason to strictly depart from these sources. TheBartgry (talk) 10:07, 21 September 2020 (UTC)

The term “pi-stacking” is widely missued as Martinez and Iverson make clear. Calculations show that the face-to-face orientation is electrostatically unfavorable. Furthermore, the avaiable experimental data (e.g., crystal structures) support that the staggered orientation is far more common than face-to-face orientation. The "evidence for" section of this article is actually "evidence against". I have revised the lead and the "evidence" section heading to make that clear. Boghog (talk) 10:20, 21 May 2022 (UTC)

Content added by one ephemeral editor

Editor Emily ricq, probably a student, added the following, which should be scrutinized:

Evidence for pi stacking

The benzene dimer is the prototypical system for the study of pi stacking, and is experimentally bound by 2-3 kcal/mol in the gas phase with a separation of 4.96 Å between the centers of mass. This distance is notable as it is outside the van der Waals radius. The small binding energy makes the benzene dimer difficult to study experimentally, and the dimer itself is only stable at low temperatures and is prone to cluster.

Other evidence for pi stacking comes from X-ray crystal structures. Perpendicular and offset parallel configurations can be observed in the crystal structures of many simple aromatic compounds. Similar offset parallel or perpendicular geometries were observed in a survey of high-resolution x-ray protein crystal structures in the Protein Data Bank. Analysis of the aromatic amino acids phenylalanine, tyrosine, histidine, and tryptophan indicates that dimers of these side chains have many possible stabilizing interactions at distances larger than the average van der Waals radii.

Geometric configurations

The preferred geometries of the benzene dimer have been modeled at a high level of theory with MP2-R12/A computations and very large counterpoise-corrected aug-cc-PVTZ basis sets. The two most stable conformations are the parallel displaced and T-shaped, which are essentially isoenergetic and represent energy minima. In contrast, the sandwich configuration maximizes overlap of the pi system, is least stable, and represents an energetic saddle point. This later finding is consistent with a relative rarity of this configuration in x-ray crystal data.

The relative binding energies of these three geometric configurations of the benzene dimer can be explained by a balance of quadropole/quadrople and London dispersion forces. While benzene does not have a dipole moment, it has a strong quadrapole moment. The local C-H dipole means that there is positive charge on the atoms in the ring and a correspondingly negative charge representing an electron cloud above and below the ring. The quadropole moment is reversed for hexafluorobenzene due to the electronegativity of fluorine. The benzene dimer in the sandwich configuration is stabilized by London dispersion forces but destabilized by repulsive quadropole/quadropole interactions. By offsetting on benzene ring, the parallel displaced configuration reduces these repulsive interactions and is stabilized. The T-shaped configuration enjoys favorable quadropole/quadruple interactions, as the positive quadropole of one benzene ring interacts with the negative quadropole of the other. The benzene rings are furthest apart in this configuration, so the favorable quadropole/quadropole interactions evidently compensate for diminished dispersion forces.

Quadrapole moments of benzene and hexafluorobenzene. The polarity is inverted due to differences in electronegativity for hydrogen and fluorine relative to carbon.

Substituent effects

The ability to fine-tune pi stacking interactions would be useful in numerous synthetic efforts. One example would be to increase the binding affinity of a small-molecule inhibitor to an enzyme pocket containing aromatic residues. The effects of substituents on pi stacking interactions is difficult to model and a matter of debate.

Electrostatic model

An early model for the role of substituents in pi stacking interactions was proposed by Hunter and Sanders. They used a simple mathematical model based on sigma and pi atomic charges, relative orientations, and van der Waals interactions to qualitatively determine that electrostatics are dominant in substituent effects. According to their model, electron-withdrawing groups reduce the negative quadropole of the aromatic ring and thereby favor parallel displaced and sandwich conformations. Contrastingly, electron donating groups increase the negative quadropole, which may increase the interaction strength in a T-shaped configuration with the proper geometry. Based on this model, the authors proposed a set of rules governing pi stacking interactions which prevailed until more sophisticated computations were applied.

Experimental evidence for the Hunter-Sanders model was provided by Siegel et al. using a series of substituted syn- and anti-1,8-di-o- tolylnaphthalenes. In these compounds the aryl groups "face-off" in a stacked geometry due to steric crowding, and the barrier to epimerization was measured by nuclear magnetic resonance spectroscopy. The authors reported that aryl rings with electron-withdrawing substituents had higher barriers to rotation. The interpretation of this result was that these groups reduced the electron density of the aromatic rings, allowing more favorable sandwich pi stacking interactions and thus a higher barrier. In other words, the electron-withdrawing groups resulted in "less unfavorable" electrostatic interactions in the ground state.

Urch et al. applied a more sophisticated chemical double mutant cycle with a hydrogen-bonded “zipper” to the issue of substituent effects in pi stacking interactions. This technique has been used to study a multitude of noncovalent interactions. The single mutation, in this case changing a substituent on an aromatic ring, results in secondary effects such as a change in hydrogen bond strength. The double mutation quantifies these secondary interactions, such that even a weak interaction of interest can be dissected from the array. Their results indicate that more electron-withdrawing substituents have less repulsive pi stacking interactions. Correspondingly, this trend was exactly inverted for interactions with pentafluorophenylbenzene, which has a quadruple moment equal in magnitude but opposite in sign as that of benzene. The findings provide direct evidence for the Hunter-Sanders model. However, the stacking interactions measured using the double mutant method were surprisingly small, and the authors note that the values may not be transferrable to other systems.

In a follow-up study, Hunter et al. verified to a first approximation that the interaction energies of the interacting aromatic rings in a double mutant cycle are dominated by electrostatic effects. However, the authors note that direct interactions with the ring substituents, discussed below, also make important contributions. Indeed, the interplay of these two factors may result in the complicated substituent- and geometry-dependent behavior of pi stacking interactions.

Double mutant cycle used by Hunter et al. to probe T-shaped pi stacking interactions

Direct Interaction model

The Hunter-Sanders model has been criticized by numerous research groups offering contradictory experimental and computational evidence of pi stacking interactions that are not governed primarily by electrostatic effects.

The clearest experimental evidence against electrostatic substituent effects was reported by Rashkin and Waters. They used meta- and para-substituted N-benzyl-2-(2-fluorophenyl)-pyridinium bromides, which stack in a parallel displaced conformation, as a model system for pi stacking interactions. In their system, a methylene linker prohibits favorable T-shaped interactions. As in previous models, the relative strength of pi stacking interactions was measured by NMR as the rate of rotation about the biaryl bond, as pi stacking interactions are disrupted in the transition state. Para-substituted rings had small rotational barriers which increased with increasingly electron-withdrawing groups, consistent with prior findings. However, meta-substituted rings had much larger barriers of rotation despite having nearly identical electron densities in the aromatic ring. The authors explain this discrepancy as direct interaction of the edge of hydrogen atoms of one ring with the electronegative substituents on the other ring. This claim is supported by chemical shift data of the proton in question.

Much of the detailed analyses of the relative contributions of factors in pi stacking have been borne out by computation. Sherill and Sinnokrot reported a surprising finding using high-level theory that all substituted benzene dimers have more favorable binding interactions that benzene dimer in the sandwich configuration. Later computational work from the Sherill group revealed that the substituent effects for the sandwich configuration are additive, which points to a strong influence of dispersion forces and direct interactions between substituents. It was noted that interactions between substituted benzenes in the T-shaped configuration were more complex. Finally, Sherril and Sinnokrot argue in their review article that any semblance of a trend based on electron donating or withdrawing substituents can be explained by exchange-repulsion and dispersion terms.

Houk and Wheeler also provide compelling computational evidence for the importance of direct interaction in pi stacking. In their analysis of substituted benzene dimers in a sandwich conformation, they were able to recapitulate their findings using an exceedingly simple model where the substituted benzene, Ph-X, was replaced by H-X. Remarkably, this crude model resulted in the same trend in relative interaction energies, and correlated strongly with the values calculated for Ph-X. This finding suggests that substituent effects in the benzene dimer are due to direct interaction of the substituent with the aromatic ring, and that the pi system of the substituted benzene is not involved. This latter point is expanded upon below.

Houk and Wheeler's computational model of substituent direct interactions in pi stacking.

In summary, it would seem that the relative contributions of electrostatics, dispersion, and direct interactions to the substituent effects seen in pi stacking interactions are highly dependent on geometry and experimental design. The lack of consensus on the matter may simply reflect the complexity of the issue.

Requirement for aromaticity

The conventional understanding of pi stacking involves quadropole interactions between delocalized electrons in p-orbitals. In other words, aromaticity should be required for this interaction to occur. However, several groups have provided contrary evidence, calling into question whether pi stacking is a unique phenomenon or whether it extends to other neutral, closed-shell molecules.

In an experiment not dissimilar from others mentioned above, Paliwal et al. constructed a molecular torsion balance from an aryl ester with two conformational states. The folded state had a well-defined pi stacking interaction with a T-shaped geometry, whereas the unfolded state had no aryl-aryl interactions. The NMR chemical shifts of the two conformations were distinct and could be used to determine the ratio of the two states, which was interpreted as a measure of intramolecular forces. Interestingly, the authors report that a preference for the folded state is not unique to aryl esters. For example, the cyclohexyl ester favored the folded state more so than the phenyl ester, and the tert-butyl ester favored the folded state by a preference greater than that shown by any aryl ester. This suggests that aromaticity is not a strict requirement for favorable interaction with an aromatic ring.

Other evidence for non-aromatic pi stacking interactions results from computation analysis. Grimme reported that the interaction energies of smaller dimers consisting of one or two rings are very similar in for both aromatic and saturated compounds. This finding is of particular relevance to biology, and suggests that the contribution of pi systems to phenomena such as stacked nucleobases may be overestimated. However, it was shown that an increased stabilizing interaction is seen for large aromatic dimers. As previously noted, this interaction energy is highly dependent on geometry. Indeed, large aromatic dimers are only stabilized relative to their saturated counterparts in a sandwich geometry, while their energies are similar in a T-shaped interaction.

A subtler approach to modeling the role of aromaticity was taken by Bloom and Wheeler. The authors compared the interactions between benzene and either 2-methylnaphthalene or its non-aromatic isomer, 2-methylene-2,3-dihydronaphthalene. The later compound provides a means of conserving the number of p electrons but removing the effects of delocalization. Surprisingly, the interaction energies with benzene are higher for the non-aromatic compound, suggesting that pi-bond localization is favorable in pi stacking interactions. The authors also considered a homodesmotic dissection of benzene into ethylene and 1,3-butadiene and compared these interactions in a sandwich with benzene. Their calculation indicates that the interaction energy between benzene and homodesmotic benzene is higher than that of a benzene dimer in both sandwich and parallel displaced conformations, again highlighting the favorability of localized pi-bond interactions. These results strongly suggest that aromaticity is not required for pi stacking interactions in this model.

Homodesmotic dissection of a) 2-methylnaphthalene and b) benzene used by Bloom and Wheeler to quantify the effects of delocalization on pi stacking.

Even in light of this evidence, Grimme concludes that pi stacking does indeed exist. However, he cautions that smaller rings, particularly those in T-shaped conformations, do not behave significantly differently from their saturated counterparts, and that the term should be specified for larger rings in stacked conformations which do seem to exhibit a cooperative pi electron effect.

Applications of pi stacking

A powerful demonstration of stacking is found in the buckycatcher. This molecular tweezer is based on two concave buckybowls with a perfect fit for one convex fullerene molecule. Complexation takes place simply by evaporating a toluene solution containing both compounds. In solution an association constant of 8600 M⁻¹ is measured based on changes in NMR chemical shifts.

Crystal structure of a fullerene bound in a buckycatcher through aromatic stacking interactions. Reported by Sygula and coworkers.

Pi stacking is prevalent in protein crystal structures, and also contributes to the interactions between small-molecules and proteins. As a result, pi-pi and cation-pi interactions are important factors in rational drug design. One example is the FDA-approved acetylcholinesterase (AChE) inhibitor Tacrine which is used in the treatment of Alzheimer's disease. Tacrine is proposed to have a pi stacking interaction with the indolic ring of Trp84, and this interaction has been exploited in the rational design of novel AChE inhibitors.

Crystal structure of Tacrine bound to acetylcholinesterase (PDB accession: 1ACJ) visualized using USCF Chimera. A pi stacking interaction between Tacrine (blue) and Trp84 (red) is proposed.

References

--Smokefoot (talk) 13:59, 3 October 2024 (UTC)

Split proposal

This article is mainly about benzene---benzene dimerization and related arene chem. As the article explains, such stacking is rare and the article is mainly a handwringing discussion rationalizing the absence of this benzene--benzene stacking (many of us who are trained in organic conclude that arenes must stack pi-pi, but they very rarely do). The article is an organic perspective of one niche of stacking. According to Greenwood and Earnshaw's "Chemistry of the Elements", one finds many cases of stacking in chemistry. Several Li3(NR)3 rings dimerize by stacking. Some forms of aluminium hydroxide, Al(OH)₃, and alumina, Al₂O₃, are described as stacking of Al-O(H) groups. Several comments on Graphite intercalation compounds refer to its stacking. Silicon carbide in some forms is described as stacked. Some metal carbides are stacked. [Pt(CN)₄]^2- and Krogmann's salt. Stacking describes vanadyl complexes that interact via V=O---V=O---V bonding. So, I propose to insert these authenticated examples in place of what is here.

Now, if others are agreeable to the above, the problem is what to do with the current content? One possibility is to create an article on Benzene dimer and related phenomena. The literature on benzene dimer is substantial (700 refs on SciFinder). But better might be Pi-stacking, which is currently a redirect to this article. The transfer of the current content to pi-stacking is supported by this quote from the introduction of a highly cited publication (McGaughey, Georgia B.; Gagné, Marc; Rappé, Anthony K. (1998). "π-Stacking Interactions". Journal of Biological Chemistry. 273 (25): 15458–15463. doi:10.1074/jbc.273.25.15458. PMID 9624131.) "Attractive nonbonded interactions between aromatic rings are seen in many areas of chemistry, and hence are of interest to all realms of chemistry. Porphyrin aggregation (1), the conformation of diarylnaphthalenes (2) and phenylacetylene macrocycles (3), and the strength of Kevlar (4) can be attributed, at least in part, to aromatic-aromatic interactions."

Summary proposal: 1) replace most this article with content on stacking from Greenwood and Earnshaw's Chemistry of the Elements 2) transfer most of the current content to Pi-stacking.

--Smokefoot (talk) 18:23, 3 October 2024 (UTC)

• Support at a minimum offloading the majority of the existing content to "pi-stacking". That is possibly the major chemical aspect of stacking in chemistry, definitely the major focus on this article that we currently have (but not the only focus), and easily a notable subtopic per WP:SPLIT. That leaves a summary of that subtopic here, along with other subtopics that don't merit their own articles at this time each in their own section. DMacks (talk) 16:37, 5 October 2024 (UTC)
• @Amakuru: you previously undid an explained page-move of this article without (as far as I can find) any comment. Would you care to comment now? DMacks (talk) 16:42, 5 October 2024 (UTC)
• Comment While looking at the article-history, I found we also have a Pi-interaction article. Might be good to make sure that one correctly points to whatever relevant "stacking" articles we eventually have. DMacks (talk) 16:50, 5 October 2024 (UTC)