Building Molecules: Why Shape Matters

Chemists are molecular architects: they design and build the molecules that are used in medicines, materials, fuels, and technologies. But building the desired molecule is not always easy. Like building blocks, molecules have particular places where they can connect. These are called their reactive parts. When reactive parts form a new connection, called a chemical bond, the molecule reacts and is transformed into a new molecule. However, some molecules are flexible, like tiny pieces of string, so their reactive parts do not always come close together and align properly. Chemists therefore look for clever ways to guide molecules into the shapes needed for these parts to connect. In this article, we show how pumpkin-shaped molecules can help solve this problem.

Meet the Molecular Pumpkins!

In our chemistry lab, it is Halloween all year round, but the pumpkins we fill are not for candy—they are for molecules. These special pumpkins are called cucurbiturils [1]. Cucurbiturils (CBs) received this name because their shape reminded chemists of pumpkins, which belong to the plant family Cucurbitaceae. They were first made in the laboratory more than 100 years ago, in 1905, but their structure was only fully understood much later, in 1981, when they received this name. Chemists often describe them as pumpkin-shaped because they are round, hollow, and have openings at the top and bottom (Figure 1A), a bit like carved pumpkins. So, we often call them molecular pumpkins.

CBs can have different sizes, represented by a number in square brackets, such as CB[5], CB[6], CB[7], or CB[8]. This number tells us how many repeating units or building blocks make up the molecular pumpkin (Figure 1B). For example, CB[7] is made from seven repeating units, giving it a cavity size between the smaller CB[6] and the larger CB[8].

CBs also have a spooky power: they can trap other molecules inside them, just like a pumpkin-shaped trick-or-treat bucket can hold candy. In science, this is called host–guest chemistry [2]: the CB is the host, and the trapped molecule is the guest. Larger CBs can trap larger guests, while smaller ones can accommodate small guests.

But why do they trap molecules at all? Because tiny spaces can change the way molecules behave …

The Challenge: Helping Molecules Make Rings

In one special reaction we study, a molecule needs to bend and twist until its two reactive ends, connected by a chain, meet to form a new ring. This reaction helps chemists build important ring-shaped molecules, which are found in many medicines, natural products, and useful materials. But bending into the right shape has an energy cost, so many molecules do not easily adopt the required shape. Instead, they keep their reactive ends far apart and stay unreactive.

Imagine a scarecrow standing in a field. Its hands (our reactive ends) are stretched far apart. That is how our free molecules usually look in solution (Figure 2). For the reaction to work, those “hands” need to clap, but this rarely happens spontaneously. Most of the time, they stay stretched out. If we can help these reactions happen faster and more easily, we may be able to build valuable molecules more efficiently. So, how can we help our scarecrow clap its hands? We put it into the molecular pumpkin!

The Trick

When a molecule enters a CB, it must bend to pass through the small opening and fit inside the cavity. Its “hands” (the reactive ends) come closer together—precisely what is needed to react!

Inside the CB, the molecule is held in just the right shape for the reaction to happen (Figure 3). Once in this special geometry, the reaction happens up to 10,000 times faster. That is like turning a slow crawl into a lightning sprint! So, the pumpkin does not do the reaction itself. It simply gives the molecule a little nudge into the right shape for it to happen.

Why do Molecules Like Going Inside the CB?

We perform our experiments in water, but many of the molecules we work with do not like water. They prefer to avoid it and stay dry. The inside of a CB is a water-hating space (the word for this is hydrophobic, which literally means “afraid of water”) [3]. So, when a hydrophobic molecule spots this perfect hideout, it quickly dives inside to escape the surrounding sea of water. Once inside, the molecule stays dry and is gently pushed into the proper shape for the reaction, bringing its two reactive ends together and accelerating the reaction.

The Science Behind the Trick

Now that you know what happens, we will tell you why it happens.

Think about your room. Before you play in it, it looks perfectly tidy; every toy is in its box. But after playing for a while, toys end up everywhere: on the floor, under the bed, between the blankets. There are many ways for a room to be messy, but few ways for it to be tidy. The word for these possible arrangements and their associated order/disorder is entropy [4]. A tidy room has lower entropy, while a very messy room is higher in entropy.

Our molecules behave similarly. In solution, they twist and stretch freely. That is their “messy room” state. They love having space and being floppy, like our scarecrow with its arms happily spread wide. But for the reaction to happen, the molecule needs to hold a particular shape: its two reactive “hands” must come closer. Achieving that specific shape has an energy cost, because the molecule must give up many of its possible shapes. In our room analogy, it is like tidying up: there are fewer ways for everything to be neatly arranged than messy. So, most of the time, the molecule chooses the easy option: staying stretched out and, therefore, unreactive.

This is where the pumpkin reveals its trapping trick.

When the molecule squeezes into the CB, it suddenly has much less space to move and can adopt only a few shapes. The pumpkin holds the reactive ends closer together, helping the molecule reach an ideal shape to react. In other words, the pumpkin helps the molecule “get organized”, making the reaction go thousands of times faster.

This idea is called the Circe effect, named after Circe, a sorceress in Greek mythology who invited visitors into her house and transformed them once they were inside. Our CB does something similar at the molecular level: it traps a flexible molecule inside its cavity and holds it in a shape better suited for reaction.

Thanks to this trapping trick, a molecule that usually refuses to react becomes quick, efficient, and ready—all inside a tiny molecular pumpkin.

A Peek Inside the Lab

How do we know all this is happening? In our lab, we use specialized tools that help us “see” what molecules are doing in solution, even though they are far too small to be visible to the naked eye. One of these tools is called Nuclear Magnetic Resonance (NMR) spectroscopy. You can think of it as a super-powerful fingerprint scanner for molecules. NMR helps us see whether a molecule is free in water, trapped inside a CB, or has already reacted.

When the reaction occurs outside the pumpkin, it is very slow, sometimes so slow that the product cannot be detected within a reasonable time using NMR. But as soon as we add the CB, everything changes. We can detect new signals showing that the molecule has entered the CB cavity and reacted to form the desired product. What used to take weeks or months can now happen in just a few hours!

The best part is that the molecular pumpkin does not get used up. After helping one molecule react, the CB can release the new product back into the water and then help another molecule, and the next one. Substances that speed up reactions without getting used up are called catalysts.

Why it Matters: Nature’s Tricks in Our Lab

Nature already has its own super-catalysts: enzymes [5]. Enzymes are special proteins in our bodies that speed up reactions without being used up themselves, by holding molecules in just the right way—just like our CBs do.

By studying molecular pumpkins, we are learning how to mimic enzymes using simple synthetic containers. This not only improves our understanding of natural systems by also helps chemists design better reactions, make new molecules and materials in more efficient ways.

Thus, trick or treat? With CBs, we get both: the trick of mimicking enzymes, and the treat of holding molecules inside our synthetic enchanted pumpkins, where their reactive parts are brought together in just the right position to connect and form rings much faster.

Glossary

Molecule: ↑ A group of atoms linked together. Molecules make up everything around us, including air, water, food, medicines, plants, animals, or even our own bodies.

Cucurbiturils: ↑ Pumpkin-shaped host molecules with hollow cavities that can hold guest molecules.

Host–guest Chemistry: ↑ When one molecule (the host) has a hollow space that can hold another molecule (the guest) inside it, like a tiny molecular house.

Hydrophobic: ↑ Describes molecules that do not mix well with water and tend to avoid contact with it.

Entropy: ↑ A measure of how spread out energy and matter are. Higher entropy means things are more mixed up, less organized, and less able to do useful work.

Nuclear Magnetic Resonance (NMR) Spectroscopy: ↑ A technique that uses strong magnets and radio waves to reveal how atoms are arranged in a molecule without damaging it—like a special camera that can see inside it.

Catalyst: ↑ A special helper molecule that makes a reaction go faster without being used up, so it can work again and again.

Enzyme: ↑ A natural catalyst found in living organisms that modulates the rate of biological reactions inside our body.

Conflict of Interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

K. V. H. thanks the European Union (Horizon 2020 Marie Skłodowska- Curie COFUND grant agreement No. 801474) and Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/ 10.13039/501100011033, CEX2019-000925-S). We also thank CERCA Programme/Generalitat de Catalunya and ICIQ Foundation.

AI Tool Statement

The author(s) declared that Generative AI was not used in the creation of this manuscript. AI (GPT-5.1) was used to generate individual visual elements (the scarecrows and pumpkins). These elements were subsequently incorporated into figures assembled, reviewed, and edited by the authors.

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