The most challenging problem for fresh organic chemistry students to overcome is the vast scale of the topic. Introductory organic chemistry books are well over a thousand pages long, and the students have to absorb huge amounts of material. A synthetic question puts all of this knowledge to the test. It asks the student: “If you wanted to make this particular molecule (picture given) from ‘scratch’ – simpler chemicals that you could easily buy – how would you do it?” What chemicals would be necessary, and how many steps would it take? Would you have to heat or chill the reaction flask? Some synthetic pathways require upwards of ten steps, all in a row, starting with a very simple chemical building block and gradually transforming it step-wise into the desired product.
These questions challenge students because their minds are so awash in the sea of learned reactions and structures that they have difficulty designing these pathways from the beginning point. They will probably agree, after the fact, that the pathway makes sense, but coming up with it on their own seems almost possible to them. The key tool that an educator needs to give his students – in order to help them in this area – is the procedure known as retrosynthetic analysis. Some students rebel against this idea, but it’s very important that an educator be stern with his/her students and insist that they approach the problem in this fashion.
Retrosynthetic analysis involves starting not at the beginning, but at the end. Look at the final structure, the desired structure, and ask yourself how this compound could be made. Don’t worry about what the starting material would have to be to get you there, just focus on one functional group – say, a double bond – and ask yourself, how would I make that? What reactions do I know that produce double bonds? Pick one of them, and write those reactants down, and then write down what the starting material must have been, given those conditions. Then, focus on the starting material that you wrote down. Is that material simple, and commercially available? If so, congratulations: the problem is finished. If not, focus on one of its key functional groups – maybe an alcohol – and ask yourself, what reactions do I know that produce alcohols? Write those conditions down, and then write down what the starting material must have been, to get you that product. This process continues all the way back, as the starting materials get simpler and simpler, until finally you’ve reached something which is available from a chemical supplier, and acts as the initial starting material as it can be easily purchased. The synthetic pathway has been solved. Thinking about the problem “retrosynthetically” – in reverse – has revealed the solution to the student.
This approach is difficult for students, as I said, and I think it’s primarily for two reasons. First, students often don’t realize just how free organic chemistry can be. There are often multiple ways of achieving a common goal, and there is more than one “correct” answer. Compare this to subjects such as math, or even some of the other sciences, and you see how rare this is really is. This triggers confusion in the students mind, as we often see the existence of more than one correct answer as proof that something must be wrong with our reasoning. As an educator, you have to break your students from that method of thinking. Stress to your students at all times that there are multiple ways of solving just about any synthetic question, and that any answer given which is correct in its methodology and in the behavior of its atoms and electrons will be counted as correct. Give them examples; show to them just how much freedom they have when it comes to designing a reaction sequence.
The other problem students often encounter is their reluctance to doodle. It sounds crazy, but it’s true. I see more and more students with each passing year who decline to write down incorrect answers on scratch paper. If they can’t come up with the correct answer in their head, they refuse to write anything, and freeze up. This behavior absolutely needs to be broken and as an educator, you need to take a leading role. Show your students the power of doodling, of writing down incomplete and often incorrect answers as a method of ruling out those approaches. Students are not penalized based on what is on scratch paper, and they’re not wasting anything more important that a pennies worth of ink and blank sheets. They need to feel free to write down anything that comes to their mind. As long as they circle their final answer, or scratch out everything but their final answer, they will not be penalized. It is only by this process of writing down ideas – thinking with the pencil, so to speak – that I myself, an organic chemist of more than fifteen years experience, can come up with the best synthetic route. It is not a trick, it is not a crutch, it is the correct way of doing things. Students need to be shown that this method is very acceptable and that it may be the only method by which they can come up with the correct answer.
Retrosynthetic analysis is very powerful, and your students need to learn it. Teaching it to them requires that you overcome several mental barriers that students have solidly in place. By being the shining example, and reassuring them during your lectures, you will give them the confidence they need to adopt this method and you’ll be transforming them into very clever, very creative organic chemists. We definitely need more of those!