Cucurbiturils and cyclodextrins — what is the difference?

Question

One was reading about the cyclodextrins on this site and decided to further investigation on the matter. One encountered a class of molecules called cucurbiturils, which are macrocyclic molecules that make possible the binding of guests into the hole of the molecule. One did not find this too different from the cyclodextrin. Apart from structural and monomeric difference, the cucurbituril appears to be identical in function to the cyclodextrin! It appears that these two molecules are alike in their function, but this cannot be the case as they are not mentioned as equivalent in any papers that one has read.

So, what exactly is the difference between cyclodextrin and curcurbituril? Is it just that one can be larger than the other and so can include larger guests? Or is there a more important difference which one can use to decide on which one to use in what scenario? Are there binding differences between the two classes of molecules?

Answer 1

TL;DR

1. Cucurbiturils are cyclic polymers of glycoluril, while cyclodextrins are polymers of glucose.
2. The carbonyl groups of the cucurbiturils, coupled with their larger size, make associations stronger for included molecules, and extend their reach to a wide range of guests that can be included within the cavity.
3. The cucurbiturils are better at binding and including both polar molecules and charged molecules such as cations. Cyclodextrins do not do this to the same degree.
4. The size of the cucurbiturils can be engineered to be as large as 12.7Å, while the largest cyclodextrin can be about 9.5Å. This, in combination with the above factors, leads to them being excellent devices for drug delivery in a way that cyclodextrin cannot do.

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Actually, the two do have distinctions that severely impact their function as molecular hosts. All these distinctions can be derived from the "structural and monomeric difference[s]" as you state.

It is worth it to go first go over these structural differences so that their applications are clearer. Cucurbiturils are polymeric forms of glycoluril, whereas cyclodextrins are polymeric forms of glucose. The final cyclic forms of these molecules are vastly different. I draw your attention to the figure below: (1) notice the obvious shape difference between the two hosts. The cucurbituril is more or less a perfect ring (Faulkner and Kenwright actually describe it more appropriately as a barrel) $^{(4)}$, whereas the cyclodextrin can be thought of as a tapered cylinder; (2) notice that in cucurbiturils, there are carbonyl groups that are exocyclic to the main cavity of the host molecule, while cyclodextrins feature hydroxyl groups exocyclic to the cavity $^{(1)}$ (image taken from 1).

Though this may seem unassuming at first, this is a key difference in terms of the guests they can complex, and how they complex them. In aqueous solution, both cyclodextrins and cucurbituril cavities are filled with water, as confirmed by diffraction studies $^{(2)(3)}$. For neutral guests, the driving force behind the inclusion for both molecules is precisely the displacement of this water from the internal cavity and the inclusion of the guest. However, the story becomes entirely different when one talks about polar guests. Owing to the carbonyl functionality, the ion-dipole interactions between positive charges on the guest and carbonyl oxygens lining the cucurbituril cavity openings becomes a major force, whereas the peripheral hydroxyl groups in the cyclodextrins generally do not engage in strong interactions with the included guest (there are exceptions, generally these occur with amphipathic molecules). I have included a photo of a cucurbituril complex below with testosterone: notice the carbonyl group interactions (image taken from this paper.)

Indeed, it has been reported numerous times that it is the function of the size and of these numerous carbonyl groups interacting with polar regions of the host that makes cucurbiturils better at complexing many guests than the cyclodextrins $^{(5)(6)}$. For one, cucurbiturils have less of a size restriction: the size of the molecule that can be included is determined by the narrowest opening of the cucurbituril, so they can complex a wider range of guests, with polar regions stabilized by association with carbonyl groups—this has been used to great success to create many rotaxanes. For cyclodextrins, the steric effects of having a host that can only be partially included are severe, as described in this question. For two: the real interactions between hydroxyl groups of the cyclodextrin are limited only to hydrogen bond accepting and donation, whereas the cucurbituril can also engage in a broader range of ion-dipole interactions. In fact, my profile picture (and probably the most famous picture of a cucurbituril you will see) is an image of it complexing a para-xylenediammonium ion. This would never work with a cyclodextrin, for example.

As a result of all these desirable properties, cucurbiturils have been used extensively as drug delivery vehicles: for example, a number of drugs such as the TB drug Ethambutol, Dexamethasone, the anti-cancer Oxaliplatin, Lansoprazole and Omeprazole, and many others have been successfully included in a cucurbituril structure. Their release generally occurs by the displacement of the drug by another, more favorable host, usually a biological ion considering how high the cucurbituril affinity is for them. These generally interact in a way that satisfies all type of interactions: dipole, van der Waals, and hydrogen bonding $^{(9)}$.

To exemplify my point, the below table shows association constants (logK) for the cucurbiturils, the cyclodextrins, and the 18-crown-6 as a control. It should be evident how much more favored binding is with the cucurbiturils!

Species	log($K_d$) for association with $\ce{Ca^{2+}}$ (solvent: $\ce{H2O}$)
cucurbit-6-uril $^{(5)}$	2.80
β-cyclodextrin $^{(7)}$	0.633
18-crown-6 $^{(5)}$	< 0.5

This means that broadly, cucurbiturils are far, far better at binding polar molecules than cyclodextrins are. And, due to their larger size, you can fit a whole host of molecules in their cavities. They are more versatile than cyclodextrins in this regard: the largest cucurbituril (with 10 monomers) has a cavity size of 12.7Å; the largest cyclodextrin has a cavity size of 9.5Å. You can even fit a whole cucurbituril inside a cucurbituril—this has actually happened, and is called a molecular gyroscope (figure below) $^{(8)}$, and is probably up there with my favorite supramolecular constructions ever. (image taken from Wikipedia and 8.)

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1. Steed, J. W., Atwood, J. L.; Supramolecular Chemistry, 2nd Ed., Wiley, 2009.
2. . Day, A. P. Arnold, R. J. Blanch and B. Snushall, J. Org. Chem., 2001, 66, 8094
3. Saenger, W. et al.; "Structures of the Common Cyclodextrins and Their Larger Analogues — Beyond the Doughnut." Chem. Rev., Vol. 98, Issue 5, 1998.
4. Faulkner, S., Kenwright, A. M.; Supramolecular Chemistry in Medicine, in Supramolecular Chemistry: From Molecules to Nanomaterials, Wiley, 2012.
5. J. Lagona, P. Mukhopadhyay, S. Chakrabarti, and L. Isaacs, Angewandte Chemie, 2005, 44.
6. J. Lee, S. Samal, N. Selvapalam, et al., Accounts of Chemical Research 2003, 36.
7. Chen, X., Chu, Y., Gu, L., Zhou, M., & Ding, C.-F. (2020). Carbohydrate Research, 492
8. Anthony I. Day, Rodney J. Blanch, Alan P. Arnold, Susan Lorenzo, Gareth R. Lewis, and Ian Dance, Angew. Chem. Int. Ed.; 2002; 41(2)
9. Day, A. I., Collins, J. G.; Cucurbituril Receptors and Drug Delivery in Supramolecular Chemistry: From Molecules to Nanomaterials, Wiley, 2012.

Answer 2

Cyclodextrins are polymeric glucose, whereas cucurbiturils are derivatives of urea - containing nitrogen atoms besides oxygens...

So yes, different in structure and possible function in some cases.