Science historian Catherine M. Jackson discusses the origins of organic synthesis

In her new book, Molecular World: Making Modern Chemistry, chemistry historian Catherine M. Jackson brings the world of 19th-century experimentalists to life for chemists and other readers today. And in so doing, Jackson makes a compelling case for the role that laboratory experimentation still plays in shaping chemical theory.

Jackson, a professor of the history of science at the University of Oxford, began her career as a synthetic organic chemist. As a historian, she became interested in the origins of her field, which dates back to the 1800s. When Jackson revisited early organic synthesis experiments, she realized that what 19th-century chemists called synthesis does not meet the definition we use now. Her new book disentangles the history of 19th-century chemists from the modern scientific theories we often project onto the past. “This story became a search for when synthesis began and why it began,” she says.

Jackson’s research led her to the stories of three chemists: August Wilhelm von Hofmann; Albert Ladenburg; and Justus von Liebig, who invented the famous kaliapparat that’s immortalized in the American Chemical Society logo. (ACS publishes C&EN.) Jackson spoke with C&EN about what researchers get wrong when interpreting 19th-century experiments through current scientific theory, the surprising role glassware played in making modern chemistry, and whatMolecular World can tell us about how to train the next generation of scientists.

This conversation has been edited for length and clarity.

Chemists today often think about organic synthesis as being synonymous with target synthesis—choosing a specific molecule and designing a route to make it. But that’s not how it started. What was the problem that synthesis helped solve at that point in chemistry’s history?

The issue is that if you call all of those experiments organic synthesis based on a modern definition, you don’t get to understand what the people who did them thought they were doing and what that work meant to them.

Today, synthesis basically means “making stuff.” When synthesis began, it was another way of finding out what things were—specifically, organic compounds.

By 1840, chemists knew that organic compounds were made from carbon, hydrogen, sometimes oxygen, sometimes nitrogen, and other things. They knew––om a very small number of elements.

Many of those substances have very similar formulae. But quite a lot of them actually have the same formula. And the explanation for that was a thing called constitution, which is part of this whole area of chemistry that becomes structure. What synthesis can tell you—that analysis will never tell you—is how these elements are joined together in the molecule. And that is also useful for fixing formulae that are very hard to differentiate.

Organic analysis alone—the attempt to determine the composition of organic compounds—hit a complete deadlock and was never going to solve this problem. That’s why the so-called king of analysis, a guy named Justus Liebig, said, “OK, then we need something new. We’re going to keep analyzing things. But we’re also going to begin doing things we call synthesis.” So he gave that project to his protégé, August Wilhelm Hofmann.

Hofmann began developing a method of synthesis that worked by taking a family of compounds and doing the same reaction on all of them to build a taxonomy of substance. And it seems that Hofmann and one of his coauthors were the first to use the word synthesis in relation to organic compounds.

Why did you choose not to include visual diagrams of molecular structures in this book?

If you want to understand how people found something new, it’s hopeless if you already know the answer. Let’s take Justus Liebig analyzing morphine. We know a lot more about morphine today than just the formula. But when Liebig is analyzing morphine repeatedly and trying to work out how much nitrogen is in the formula, he doesn’t know when he’s got the right answer.

For another example, there’s a story at the end of the book about how Albert Ladenburg first synthesized coniine. When he was doing these reactions, he was pursuing this method that he hoped would make coniine, but he didn’t know whether the side chain was a propyl or an isopropyl group. He didn’t even know where the side chain was in the molecule. If you want to understand that struggle, I think you have to set current knowledge aside. I wanted to help my readers do that by not giving them the option.

The book introduces a phenomenon you call the glassware revolution as a driving force for innovation in 19th-century chemistry. What do you mean by that?

The glassware revolution was a shift away from products made by furnace glassblowing that you buy from an instrument maker. These apparatus were pretty expensive and quite hard to get hold of. Around the 1830s, chemists began to use glass tubing that you can shape into a lamp—or what we now call scientific glassblowing. That allowed chemists to make their own apparatus much more cheaply. And if something doesn’t work quite right, the chemist can switch it up themselves, provided they know how to blow glass. This is also the origin of group research as we know it today because it means you can have many more people doing chemistry.

One example of that is the kaliapparat that Liebig made for analyzing nitrogen in molecules such as morphine. So the glassware revolution is important for analysis and absolutely crucial for synthesis. Without this kind of apparatus, you just couldn’t have the level of control over reactions that synthesis required.

How did glassware help make experiments reproducible?

The flexibility that self-made glassware gave chemists was really important in attacking the problem of not only how to make things but also how to know what they’ve made. To my knowledge, nobody before me really thought about how 19th-century chemists actually knew what they made when they did reactions. That’s because [historians] always had the view that these chemists were somehow trying to make things through target synthesis. Whereas it’s much more like, “Well, I’ve mixed all this stuff together. It’s not a hit-and-miss process. It’s not an illogical process. I have reasons why I’m doing this reaction. But what is this stuff that I’ve made?”

When Hofmann is developing his method of synthesis, he struggles to differentiate the substances that he’s making because they often have very similar formulae. And because it’s really important for him to be able to recognize substances when he comes across them again, he is looking for a way to identify substances.

Then comes this idea that you could use melting points and boiling points to characterize substances. That’s great because they’re numbers, easy to publish, easy to recognize, and consistent from one time to another, from one person to another, from one place to another. They have to be standardized. So glassware allows chemists to define how our standard melting point is to be measured. And it’s in this process of standardization that you’re actually able to make something that’s universal—what were called constants of nature.

Where do you see the legacy of this period of chemical history in the laboratory today?

You might say that’s the most important question. Why does this history matter? In the history of 19th-century chemistry before this book, theory is what changes what chemists can do. And what I have done in this book is make an argument for how chemists worked with [existing] theory and extremely thoughtful experimentation to build new theory. This is what I call laboratory reasoning. It’s a fairly fundamental revision of what you think theory is, and there’s a connection there to how we train people.

We tend to train chemists today in a lot of theory, which is extremely powerful but which probably looks to most chemists in training as though it’s quite finished. So consider students making the transition from doing lab practicals—which are designed to work—to going into a research lab. What are they supposed to make of that prior training? This kind of history is really important in giving chemists a different view of the stable points of theory and the bits that we’re not yet quite sure about. It’s obviously very different now from how it was in the mid-19th century, but I think the principle is still an important one. If you tell people that their field has been built by great thinkers whose insights are moments of genius that produced theories that changed the field, that doesn’t really give anybody much of a clue how they might become a contributor.

By focusing on the experimental approaches—those aspects of apparatus, instrumentation, and laboratory, which are what chemists are mostly dealing with in their working lives—that’s giving a different account of how chemists make discoveries.

Ariana Remmel is a freelance writer based in Little Rock, Arkansas.