Chemistry inside the “Molecular Flask”

Common reaction flasks are the simplest, but the most useful companion to a chemist for preparing and storing chemicals. From the age of Alchemist to the modern age of chemistry, reaction flasks have undergone many changes (Figure 1).1 But so far with few exceptions, we have not experienced the influence of size and shape of the container on the properties of chemicals stored or on the kinetics of reaction occurring inside it. However, if the reactions are to be performed in a flask with similar dimension to the reactants (typically of few nanometers), then the size and shape of the flask would be the most important deciding parameters, capable of altering the reactivity and properties of the contained molecules. In the world of supramolecular chemistry and nanotechnology, these nanometer-sized vessels are termed as “molecular flask”.1.

Figure 1. (a) Reaction flasks, apparatus used by Alchemists(Carlo Lancillotti, 1681; Source: Wikipedia). (b) “An Alchemist in his Workshop,” by David Teniers II, depicts alchemy in the 17th century (Chemical Heritage Foundation, Source: The New York Times). (c) Modern flasks for storing and doing chemical reaction. (d) Sophisticated chemistry laboratory (Source: IISER Bhopal). 

Inspiration from nature’s molecular flask

‘Cell’ is the tiniest but most sophisticated laboratory in our known universe. In the ‘cell’ laboratory, ‘enzymes’ are the well-equipped reaction flasks, in which verities of chemical transformations take place with exceptional atomic precessions. It’s a matter of strange that the ‘seemed-impossible’ complicated reactions are bread and butter to them. What is the ‘secret’?

In 1913, German biochemist Michaelis and Canadian physician Menten investigated the activity of enzyme ‘catalyze’ and proposed the famous ‘lock & key’ model for enzyme catalysis (Figure 2).2 In 1948, Pauling proposed that the functional groups at the ‘active site’ of catalyst along with the size and shape of the enzyme ‘cavity’ are equally responsible for the remarkable selectivity to the reaction.3 Ten years letter, American biochemist Koshland suggested a modification to the ‘lock and key’ model and proposed that enzymes having flexible structures, continuously reshape their active sites by interacting with the substrates (Figure 2).2 Hence, the ‘induced fit’ model indicates that nature’s molecular flasks are exceptionally smart and intelligent to judge the substrate and act accordingly. In supramolecular chemistry, the phenomenon is termed as ‘guest-recognition’.

Figure 2. Cartoon representation of (a) ‘lock and key’ and (b) ‘induced fit’ model (inset: active site of TEV protease enzyme).

These initial ideas inspired the synthetic and supramolecular chemists to develop the artificial catalysts having substrate encapsulating cavity leading to selective chemical transformations. However, until now artificial catalysts do not come close to the catalytic efficiency and selectivity displayed by the enzymes. But there is no harm to dream for it!

Molecular Flask: Capsules to Cages

Molecules or assembly of molecules with hollow structures that encapsulate small molecular guests within their cavities are termed as ‘molecular flasks’ or ‘molecular container’.1 Since the nineteenth century, researchers around the globe have been investigating the application of molecular flasks as ‘nanoreactors’. Large arrays of molecular flasks are available based on their topologies, building blocks, and ways to assemble as a container. Cyclodextrins, cucurbiturils, crown ethers, organic cages, etc.are the discrete molecules with shape persistent cavity (Figure 3a-3b).3,4 On the other hand, H-bonded capsules, hydrophobicity driven nano-assemblies, coordination cages are the self-assembled containers with bigger cavities (Figure 3c-3e).3,4 There are few examples of ‘giant’ molecular flasks with charming ‘Archimedean topology’ (Figure 3e).5 A teaspoon of powder having some of these molecular containers provide an internal surface area which is equal or higher than that of the entire football field (~4000 m2/g)!

Figure 3. Structural representation of some of the well-known molecular flaskswith diverse topologies.

Molecular Flask as Nanoreactor

How molecular flask accelerate the reaction rate? 

The rate of chemical reactions can be enhanced by increasing the local concentration of reactants within a cavity. Compartmentalization can assist a local increase in reagent concentration, which increases the probability of events leading to chemical transformation. For example, Patra and coworkers demonstrated that amine cage (Cg-Am, Figure 3b) can trap co-catalyst (Br-, tetra-n-butyl ammonium bromide) and CO2 inside its cavity. It can also activate the substrate epoxide through H-bonding. In the presence of Cg-Am, epoxides can be easily converted to the cyclic carbonate due to the co-existence of the substrates, catalyst, and co-catalysts inside the cavity (Figure 4).6

Figure 4: Conversion of epoxide and CO2 into cyclic organic carbonates catalyzed by amine cage (Cg-Am).

Confinement can also stabilize interactions between catalysts and reagents that do not like each other in solution. For example, cationic [Ru(bpy)3]2+photocatalystand cationic dye methylene blue (MB) electrostatically repulse each other in solution and consequently react poorly (yield: ~20 %). However, an anionic coordination cage, PCC-2 can accommodate these two cationic species in its cavity, and thus enabling [Ru(bpy)3]2+ to catalyze the photo-degradation of MB dye (Figure 5).7

Figure 5. Photocatalytic decomposition of cationic dye, methylene blue by [Ru(bpy)3]2+ in presence of porous coordination cage (PCC-2).

Confinement can also be used to pre-organize flexible molecules into a folded conformation to attain cyclized product, which would be challenging or unthinkable in bulk solution. For example, encapsulation of long-chain amino acids into the vase-shaped de Mendoza cavitand leads to the folding of the guest such that their reactive end-groups are pointed close to one another. This leads to the formation of lactams.8 Whereas, reaction without the cavitand gives mostly a mixture of oligomeric products (Figure 6a). The same cavitand with ‘wider mouth’ conformation can catalyze the formation of macrocyclic urea which is highly challenging to do in simple bulk phase (yield with cavitand: 84%, without cavitand: 13%, Figure 6b).8 Folding of long-chain molecules inside the molecular flask can also facilitate remote functionalization.

Figure 6. (a) Synthesis of cyclic lactam inside the ‘vase’ shaped de Mendoza’s cavitand. (b) Synthesis of macrocyclic urea inside the ‘wider mouth” de Mendoza cavitand.

 How molecular flask enhance or alter the selectivity of a chemical reaction?

Performing the reactions within molecular flask can enhance or alter the selectivity for certain products over others and sometimes the formed products are completely different from the products obtained from the bulk reaction. When reactions occur under confinement, constriction can limit the size and shape of the resulting products which leads to regio- as well as stereoselectivity. For example, Fujita’s octahedral cage (Figure 3d) can selectively recognize two different substrates, i.e., 9-(hydroxymethyl)-anthracene (9-HMA) and N-cyclohexylmaleimide (N-CHM), at a time in its cavity. Suspending 9-HMA and N-CHM in an aqueous solution of the equal stoichiometry of the cage has resulted in the selective formation of Cage ⊂ 9-HMA.N-CHM (Figure 7).1,3 Upon warming the reaction, the syn-1,4-Diels-Alder (D-A) adduct is formed in 98%. Whereas, bulk solution reaction yields the 1,9-D-A adduct, in 44% of yield. The unusual regio-and stereo-selectivity in the encapsulated D-A reaction is explained by the fixed orientation of both the substrates within the Fujita’s cage, preventing interaction at the 9,10 position of the anthracene (9-HMA). This is a perfect example of preorganization within the nanoreactor which prevents the formation of the most energetically favoured product.

Figure 7. Diels-Alder (D-A) reaction inside and outside the octahedral Fujita’s cage (inset: crystal structure of product encapsulated Fujita’s octahedral cage).

Understanding of ‘Encapsulation Effect” through Basic Physical Chemistry

To understand the effect of ‘encapsulation’ on the reaction kinetics and selectivity, let’s consider a simple bimolecular reaction occurring in the bulk phase where substrates A and B react to give product C . Then the general rate-equation will be as follows (Eq. 1):

Eq. 1

where [x] is the concentration of the respective species and ka is the rate constant.


On the other hand, if reactions take place inside a molecular flask, then we need to consider the substrate encapsulation and product release in-and-out of the nanoreactor (NR). Generally, it was found that the reaction between A and B inside the nanoreactor (NR) is the rate-determining step (RDS) and with the analogy of Michaelis-Menten kinetics, the rate equation will be (Eq. 2, Figure 8)

Eq. 2

where, A.B ⊂ NR and C ⊂ NR are the encapsulated substrate and product in the nanoreactor (NR), respectively. kb is the rate constant of the RDS.

According to Arrhenius’ equation, the rate-constant,k is a function of thermodynamic parameters, i.e., the Gibbs free energy (∆G#), the enthalpy (∆H#), and the entropy (∆S#) of activation (Eq. 3, 4):

Eq. 3 & 4

where, R = gas constant,c = a constant,and T = temperature.


Figure 8. (a) Energy profile diagram of bimolecular reaction inside the molecular flask/nanoreactor (NR) and in the bulk solution. (b) Cartoon representation of reaction kinetics in the absence and presence of nanoreactor (NR).

Now, reactions inside the molecular flask can face two extreme scenarios3:

1) If the nanoreactor does not change the activation parameters (i.e.,∆G# NR = ∆G#bulk), then from Eq. (1) and (2), the rate constant remains the same, ka = kb and the difference in the rate is due to the difference in concentrations: [(NR ⊂ A.B)] and [A].[B]. The ‘encapsulation’ will only affect the preorganization of substrates leading to the intramolecular reaction instead of intermolecular reaction.

2) If the nanoreactor changes the activation parameters (i.e.,∆G# NR < ∆G#bulk), i.e., it can stabilize the transition states (∆G#) of the reactions, then the reaction rate will be faster compared to the bulk solution. The decrease in the activation barrier is due to the enthalpic stabilization (∆H#) via noncovalent interactions (H-bonding, hydrophobic, ion-p interactions, electrostatic interactions, etc.) between the transition state and the nanoreactor. The entropy (∆S#) also plays a crucial role in stabilizing the transition state. The specific size, shape, and chemical environment of the confined cavity help the encapsulated substrates to effectively preorganize towards the transition state and reduce the potential negative entropy of a reaction.

On the other hand, to explain the selectivity of the reaction, the following logic can be considered. The specific interactions between the molecular flask and the encapsulated substrates can alter the activation energy barrier ∆G#of products D, and E compared to the bulk (Figure9a). The ‘encapsulation effect’ can stabilize the transition state leading to product E and thus favouring its formation. On the contrary, the same effect can destabilize the transition state leading to product D (because of improper fitting between the substrate and cavity of NR) and thereby favouring the formation of the other product E (Figure9b).

Figure 9. Energy profile diagram of (a) non-selective and (b) selective chemical transformations in absence and presence of nanoreactor.

Future Prospect

So far we have seen the homogeneous catalysis using the molecular flask. But for the real-time application, we need robust heterogeneous recyclable catalysts. Recently, cavitands based porous materials [metal organic frameworks (MOFs), covalent organic frameworks (COFs), porous organic polymers (POPs)] are reported for catalysis applications.9  Not only catalysis, owing to guest-responsive properties, cavitand-based polymers also can be used for charge-specific size-selective molecular separation and water purification.9,10 Creating new interfaces between the supramolecular chemistry and other branches of science will pave the way for space-age applications like enzyme mimetic catalysis, drug delivery to developing artificial molecular machines. Famous physicist, Richard P. Feynman said, “If we want to solve a problem that we have never solved before, we must leave the door to unknown ajar.

Arkaprabha Giri

References:

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  2. https://www.wikipedia.org
  3. Koblenz, T. S.; Wassenaar, J., Reek, J. N. H.,Chem. Soc. Rev.2008, 37, 247.
  4. Grommet, A. B.; Feller, M.; Klajn, R., Nat. Nanotechnol. 2020, 15, 256.
  5. (a) Fujita, D.; Ueda, Y.; Sato, S.; Mizuno, N.; Kumasaka, T.; Fujita, M., Nature2016, 540, 563, (b) Byrne, K.; Zubair, M.; Zhu, N.; Zhou, X. P.; Fox, D. S.; Zhang, H.; Twamley, B.; Lennox, M. J.; Düren, T.; Schmitt, W., Nat. Commun.2017, 8, 15268.
  6. Hussain, M. W.; Giri, A.; Patra, A., Sustainable Energy Fuels2019, 3, 2567.
  7. Fang, Y.; Xiao, Z.; Kirchon, A.; Li, J.; Jin, F.; Togo, T.; Zhang, L.; Zhud, C.; Zhou, H. C., Chem. Sci. 2019, 10, 3529.
  8. Yu,Y.; Rebek, Jr. J., Acc. Chem. Res. 2018, 51, 3031.
  9. Giri, A., Hussain, M. W.; Sk., B.; Patra, A., Chem. Mater.2019, 31, 8440.
  10. Alsbaiee, A.; Smith, B. J.; Xiao, L.; Ling, Y.; Helbling, D. E., Dichtel, W. R., Nature2016, 529, 190.

About the author:

Hi! I am Arkaprabha, a Ph.D. student from IISER Bhopal. My research interest includes the design, synthesis and investigation of cavitand-based porous organic polymers for catalysis and water purification. Apart from Chemistry, I am very much fond of watching movies, reading books on science fiction and doing ‘adda’ (chit chat) with friends.

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