The Charm and Appeal of Organic Chemistry
Articles

The Charm and Appeal of Organic Chemistry

Author: Phil S. Baran, Frauke Zbikowski

Professor Phil S. Baran, Scripps Research Institute, La Jolla, CA, USA, is well known for designing methods that make it easier to synthesize complex molecules. Dr. Frauke Zbikowski, Nachrichten aus der Chemie, talked to Phil Baran about his love of organic chemistry, his research, the value of ideas, what makes a great chemist, how to develop the best synthesis, and why you get a huge return on your investment upon paying for organic chemistry.

 

A German version of the interview is published in Nachrichten aus der Chemie.

 

What makes you so passionate about organic chemistry?

Organic chemistry is unusual because of its power to let the practitioner be both an artist and a creator.

 

 

An artist in terms of a beautiful molecule?

Well, an artist in terms of how one makes that beautiful molecule and its incredible capacity for impact with very simple logic. The charm and appeal of organic chemistry are that there is still so much to be explored and discovered and, if you uncover one of its new secrets, it can have a dramatic impact on all sorts of areas of chemical science that you wouldn’t predict. So, for me, organic chemistry is kind of like a wonderful opportunity to explore and create and to make an impact.

 

 

When did you discover that organic chemistry was like art for you?

It was probably at the beginning of college, as an undergraduate at NYU in 1995. Shortly after I began doing chemistry in a lab there, I realized that this was the only thing I needed in life.

 

 

You fell in love with chemistry?

Big time. Specifically organic. It was the only thing I wanted to do: mix chemicals; do reactions; create stuff. There was always a sense of exploring the unknown. Time became so valuable because lost time was time that I could have spent exploring.

 

 

But still you managed to finish your studies, with all of the other subjects you had to do.

As quick as I could, yeah. There were a lot of other subjects that they made me study and I did just well enough to pass and no further. Organic chemistry and doing lab work was really what got me up every morning. And the other stuff was like a requirement that I grudgingly would do.

 

 

Are you still doing lab work?

Every once in a while.

 

 

What skills does a successful organic chemist need?

Probably they need intense dedication, passion, and a positive aptitude; they also need internal optimism, intellectual humility, and a desire to create. You’ll notice none of the things I mention relate to testing scores or academic aptitude.

 

 

When you choose students for your lab, you don’t look at their scores?

We have to … but now looking back over the past 14 years of doing this, there is really not a good correlation between grades and excellence in research. I think the tests are judging something different than the skills needed to survive in organic chemistry. Chemistry is a vast field and there is a lot that has to be done. So, before one enters as a graduate student, there is already an enormous body of literature needed to sort of have under one’s belt.

 

So, how do you get skilled, talented students for your lab? How do you choose them?

Well, every year, we interview the top students in the country who want to go into organic chemistry. I generally choose students based on their excitement level and how well they know what they want to do in life. Often, the best students have a clear idea of what they want to do and where they want to go by the time they go to graduate school. I also look at those who understand that their life is gonna be kind of like that of a monk in graduate school. Undergraduate research experience is a great indicator of future success.

 

 

Was it easy for you to get skilled students before you became famous?

I don’t know that I am famous. I mean, I think that Scripps is a great place to do research. People are attracted to Scripps because it is kind of like an oasis for organic chemistry, at least in the United States. So, I have benefited from people knowing that Scripps is an amazing place to do organic chemistry.

At the beginning, it was actually quite easy because there were a lot of students who were excited by embarking on something totally new with a new faculty member. So, none of the starting faculties at Scripps has ever had problems recruiting students. It is quite the opposite. You know when you are there that you have to keep yourself fresh. Otherwise, students won’t want to come to an older, more seasoned investigator. So, there is a tremendous amount of selection pressure at Scripps to stay fresh and hungry.

 

 

How do you stay “fresh and hungry”?

We do not do the same thing for a long time. I need to be extremely excited every time I get up in the morning, and I cannot have students working on projects if I am not excited to know what’s going to happen. So, we don’t have projects that are like doing them because we’re cranking the wheel and we have to do them. All of the projects we are doing are cutting edge. We have a huge variety of things going on in the lab, from terpene synthesis to methodology, to alkaloids, peptides, nucleosides, and electrochemistry. And all this just because I have attention-deficit disorder. I can’t focus on one thing for a long time because there are so many things to explore in this field that I like to go and look at something, and then move on to the next thing, just because I want to stay basically in a constant state of pre-tenure.

 

 

A constant state of curiosity as well?

Yeah, curiosity and hunger; essentially, the lab is no different from how it was 14 years ago. I am still working with students every day hand in hand. My lab is based on top of my office, so I smell the chemicals every day. My door is always open. All is pretty much the same as it was in 2003: I am always worried that we cannot make a discovery fast enough.

 

 

How do you choose your synthetic targets?

In the beginning, we found them just based on structural intrigue. Then we became more and more interested in the translational component, meaning what could society gain from getting these compounds. One thing that was always consistent from the beginning, though, was that we wanted to exit the (Smithsonian) area of natural-product synthesis. So, in the nineties, it was really important to show that you could make something and that you could make something really complicated, put it somewhere, and say: “Look, I made it”. Later, it became clear that the goal really wasn’t to make stuff anymore, just to show that it was feasible. The goal became making things to show that it could be practical; that a natural-product synthesis can offer an opportunity to make materials for which biology fails. And, to do that, you need the best synthesis; not to be the first.

 

 

What is the best synthesis?

Well, we call it aiming for the ideal synthesis.

 

 

What do you mean by this?

The ideal synthesis is where you go from your starting point to your ending point and it is direct, with fewer possible steps; no detours; no concession steps; no stopping off somewhere to get a drink. You just go straight from here to there through the shortest possible point from A to B. That is ideal.

Years ago, we became very interested in the idea of formalizing and conceptualizing how an organic chemist would do that. Before we started, it was kind of obvious. There were concepts like step economy and atom economy. However, it doesn’t take someone with more than grade-level educated to tell you: “fewer steps are better”. I mean, my eight-year-old can tell me that. So, what was missing in the community was sort of how do you do that. So, we started teaching this list of rules and then demonstrating them in syntheses, and the impact on students was quite dramatic. We started seeing proposals that looked less like 1990s chemistry and more like forward-looking, extremely short, and somewhat speculative.

 

 

Is it more than trial and error, looking for steps and substances?

When you are trying to design an ideal synthesis, the point is that it requires the chemist to be an inventor. You see the problem with a feasible synthesis is that it might require many steps because you need to be sure about things and there needs to be a level of security. You need to do protecting-group chemistry and reduction–oxidation; there are detours that you need to take. Ideal syntheses, however, often involve strategies that are quite speculative, even daring, and require you to invent new stuff.

 

 

Which means that the organic chemist needs vast knowledge about chemistry?

That’s right. One reason that I am still excited about the field is that it is gonna be a very long time before robots or artificial intelligence can ever catch up. There is a simple reason for that: computers can very well master games, like chess or Go, because they know all the rules; however, the point of organic chemistry is that you can invent new steps and computers don’t invent new steps. They play by the rules.

 

 

Could you describe your role as a teacher to your students?

I am a shoulder to cry on. I am the person that they come to when they have a huge amount of pressure, and I try to keep students from falling off the cliff, to help them spend their valuable time efficiently. Some professors are very relaxed about their student’s time. I think it is my job to use my experience to make sure that they are not wasting time. As a result, for the students, we have reduced the time to graduation by about 20 %.

 

 

That’s a lot. You have had very famous mentors, when I think of Nicolaou or Corey, what did you learn from them?

A tremendous amount, from different styles of management and mentoring. I learned from their environment and from their direct wisdom. Some people say that the old system is essentially the German system of mentorship; the way that Liebig and all those people started chemistry. That was an apprenticeship and has basically carried on to this day. I think there is value to that. There was a huge amount of basic education from them. You grow during that period and learn from them how to tackle really difficult problems and then execute them. Both of them are masters at doing that. They don’t just talk; they actually do stuff. Everybody has ideas, but you have to do it.

 

 

I have read that you have a tremendous number of publications for your relatively young age. How have you managed to write all of these publications?

Well, I don’t know if we have that many. Honestly, papers are not what get me excited. I think you have to publish some papers because students need jobs and the community needs to know what we are doing with taxpayer’s money. But we try to publish actually very little and do so in a nonfragmented way. We try to present the big-picture stories and put the whole thing in one publication.

We have a blog as well, where we put behind the scenes stuff, with special tips about how to do the reactions, so we try to put as much data out there as we can and not because we are interested in getting numbers of papers, but about quality.

 

 

How do you handle negative results or students that don’t have results? I think this occurs more often in science than positive results.

Well, if you define negative as a dead end, most of what we do is that. It is probably very little actual positive results. I think the key is teaching students what a negative result is versus a negative-positive. So a negative-negative is that the students come and say: “This didn’t work; I don’t know why.” That is pretty bad and I cannot really do anything with that. But when they say this didn’t work, but this compound was formed instead or this is exactly what happened, that will give you an idea of what to do next. So, often research at the frontiers is kind of like forensic science: try to find out what happened in a crime. If students are able to generate lots of negative-positive results, eventually they turn into positive.

 

 

How do you become successful as an organic chemist? Is it curiosity and skills or is it funding?

First, you need a lot of failures. Failure is the currency of experience. So, the best organic chemists have failed a lot. There is sort of a sheer effort component. They have seen a lot of reactions, tried a lot of things, and what finally emerges is an intuitive sense of reactivity. You almost become like a hound dog. You can sniff out the reactivity; you can look at a compound and you can sense, without even touching it, how it might react. So, the only way to do that, understand that, is to do a lot of chemistry. That’s I think the most important thing to learn: to become a successful organic chemist is to become so intuitively dialed into reactivity that you can almost feel what compounds are doing just by looking at them.

 

 

How do you respond to people who tell you that the great times of organic synthesis are over?

I think every ten years there is a lunatic who says “synthesis is mature” and sometimes they are really famous people. My response is always that they should probably just mind their own business. So, the thing that’s funny is that organic chemists, synthetic ones, in particular, are never calling for a holy war against any other field. You’ll never see an organic chemist say: “Why are we funding nanochemistry? Why are we funding materials science? Why are we funding chemical biology? Why are we funding biochemistry?”. I have never heard it. At least, I would never say or think it.

But, yeah, organic chemists are always on the defense. However, when you go to journals like Angewandte Chemie or Journal of the American Chemical Society, the most read papers are always in this field that everybody says is over and shouldn’t be funded anymore. It is just engineering, right? But yet everybody is reading these papers. And, on top of that, when I go to companies, I can see very quickly the tangible impacts of new developments in organic chemistry to industries that matter, like materials science, agrochemistry, textiles, and medicine.

So, to argue that synthesis is mature, those people have probably never interacted with a real company before. Because they don’t see what goes on. The bottleneck is still chemical synthesis. So, the problem really is that organic chemists are not very good at defending themselves.

 

 

You once said that receiving funding, especially public funding, has become difficult in recent years, and you have tended to look for private funding. Why and how will you do this?

My goal within ten years is not to rely on any taxpayer’s money to fund my lab. I think the taxpayer gets a huge return on investment for paying for organic chemistry. But the big federal funding agencies, such as NSF and NIH, might decide that they are not going to continue to fund what I am doing. So, the idea is to have a contingency plan if and when funding will stop.

 

 

And you are optimistic that private companies will fund your science?

I think they’ll need to.

 

 

Thank you very much for this interview.

 

 

Phil S. Baran, born in New Jersey, USA, in 1977, received his bachelor’s degree in chemistry from the New York University (NYU), USA, in 1997, under the supervision of David Schuster; his Ph.D. from The Scripps Research Institute, La Jolla, CA, USA, in 2001, under the supervision of K.C. Nicolaou; and his Ph.D. from Harvard University, Cambridge, MA, USA, under the supervision of Nobel Laureate E. J. Corey.

In 2003, Phil Baran became Assistant Professor and, in 2006, Associate Professor of Chemistry at the Scripps Research Institute. Since 2008, Phil Baran has been Professor of Chemistry, a member of the Skaggs Institute for Chemical Biology, and Darlene Shiley Chair in Chemistry.

Phil Baran has received numerous awards, including the Elias J. Corey Award in 2016 and the MacArthur Fellowship in 2013.

 

Selected Publications

Also of Interest

 

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