Chapter 13

Chapter 13 - CHAPTER SYNTHESIS Synthesis is really just the...

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Unformatted text preview: CHAPTER SYNTHESIS Synthesis is really just the flipside of predicting products. In any reaction, there are three groups of chemicals involved: the starting material, the reagents, and the products: , , Reagents Starting material ———> Products When the products are not shown, then you have a “predict the product” problem: Flea ents Starting material —g——> ? When the reagents are not shown, then you have a synthesis problem: ? Starting material ———> Products Now that we see the similarity between predicting products and synthesis, we real— ize that for every reaction. we need to know the same information that we needed to know for predicting products: 1. What kind of reaction? 2. What is the regiochemistry‘.’ 3. What is the stereochemistry‘? Remember that all three pieces of information are contained in the mechanism. So your starting point should always be mastery of the mechanisms, followed by a strong understanding of all three pieces of information for every reaction. By doing so, you will have the fundamental building blocks that you need to begin thinking about synthesis problems. Synthesis problems can be easy (if they are only one step) or they can be dif- ficult (if they are more than one step). When you begin learning reactions in your course, you will start to encounter synthesis problems in your textbook. At first. you will get one-step problems. and as the course progresses, you will see multistep syn- theses. ln a multistep synthesis, you can often end up with a product that looks very different from the starting material. For example, look at the following series of re- actions below. Don’t concentrate on how the changes were made. For now‘just focus 263 264 CHAPTER 13 SYNTHESIS on the fact that each reaction Changes the compound only slightly, but in the end, we end up with a product completely different from the starting material: Cl : : Starting material 0 Product 11 can only take three or four steps before the problem can get quite difficult. If you convert the sequence above into a synthesis problem, it would look like this: JY—“M If you are having trouble with synthesis problems when you first encounter them, the worst thing you can do is to give up and say: “Oh, well, I’m not good at syn— thesis problems.” As the course moves on. this attitude will slowly kill your grade in the course. To see why this is so. let’s compare organic chemistry to a game of chess. Imagine that you are learning how to play chess. You first learn about the pieces: how they are named. how to set up the board, and so on. Then you lczun how each piece moves and how they capture each other. When you start playing your first game, you realize that there is quite a bit of strategy involved. Most strategies in- volve thinking more than just one move in advance. It is not good enough to know only how to move the pieces. You also need to think about how to plan out the next few moves so that you can coordinate an attack on your opponent’s pieces. Imagine how silly it would be to take the time to learn how to move the pieces. but to then say to yourself that you are not good at strategy. Imagine thinking that you will keep playing chess, but you just won’t be good at that one aspect of the game. That would be silly, because that one aspect of the game is the whole game itself. You either need to learn how to strategize, orjttst don’t play chess. There is no iii—between. Organic chemistry is very much the same. Synthesis is all about strategizing. You need to think a few moves ahead, and you must learn how to do this. You can- not tell yourself that you are not good at synthesis problems, and therefore you will just focus on the other aspects of organic chemistry. Synthesis is organic chemistty. The second half of the course is all about learning reactions and applying them in syntheses. Everything that you have learned so far has prepared you for synthesis. The only way to become proficient at synthesis is to practice. Don’t be lazy, and don’t think that you can get through the course without learning how to propose 13.1 ONE-STEP SYNTHESES 265 syntheses. If you do, you will find that your performance in the course will spiral down to a point that will make you very unhappy. There are a few techniques that will make you feel tnore comfortable with syn- thesis problems, and there are exercises that you can go through to increase your prov ficiency in doing synthesis problems. That’s what this chapter is all about. 13.1 ONE-STEP SYNTHESES As we mentioned earlier, one—step syntheses are the first synthesis problems you will encounter. They will never be more difficult than predicting products. Before you can move on to mttltistep syntheses. you first need to feel comfortable with one-step syntheses. To do this. we need to make a list, very similar to the one we made in the pre— vious chapter on predicting products. In the list we made last chapter, we left ottt the products, so that we could repeatedly photocopy the list and fill in the products. This time, we will make a list of the same reactions, but we will leave out the reagents, so that we can repeatedly photocopy the list and get practice filling in the reagents. As you learn more and more reactions. this list will grow. With every five new reactions. you should photocopy all of the reactions that you have recorded here. Then, start filling in the reagents on the photocopy. If you cannot fill them all in, go back to the previous chapter where you recorded the reactions. Repeat this procedure whenever you have entered five new reactions. If you keep up with this exercise as the course progresses, you will be in very good shape for solving one~step synthesis problems. The hardest challenge that you will face is keeping up with the work and not waiting until the night before the exam. If you wait (as most students do). you will find it very difficult to spend the time that it takes to master this material. Don’t make that mistake. The secret to success in this course is to do a little bit every night (rather than cramming on the night before the exam). Cramtning might work well for other courses, but it doesn’t work well in or— ganic chemistry. Begin your list on the next page. For now, skipfont'artl afew pages. We have some techniques m 30 over that wit! help you solve synthesis problems. 266 CHAPTER 13 SYNTHESIS Remember not to fill in the reagents or the mechanisms. For each reaction, just draw the starting material in front of the arrow and the products after the arrow. Leave the space above the arrow empty. You will fill in the reagents when you photocopy these pages: 13.1 ONE-STEP SYNTHESES 267 Now photocopy this page, and try to fill in the reagents on your photocopied page. Now photocopy this page again, and fill in the reagents for every reaction on this page. 268 CHAPTER 13 SYNTHESIS Now photocopy this page AND the previous pages. and fill in all of the reagents. 13.1 ONE—STEP SVNTHESES 269 Now photocopy this page AND the previous pages, and fill in all of the reagents. 270 CHAPTER 13 SYNTHESIS Now photocopy [his page AND the previous pages, and fill in 11]] of the. reagoms. 13.1 ONE-STEP SYNTHESES 27 1 Now photocopy this page AND the previous pages, and fill in all of the reagents. 272 CHAPTER 13 SYNTHESIS Now photocopy this page AND the previous pages, and fill in all of the reagents. 13.1 ONE-STEP SVNTHESES 273 Now photocopy this page AND the previous pages, and fill in all of the reagents. 274 CHAPTER 13 SYNTHESIS Now photocopy this page AND the previous pages, and fill in all of the reagents. 13.1 ONE-STEP SVNTHESES 275 Now photocopy this page AND the previous pages, and fill in all of the reagents. 276 CHAPTER 13 SYNTHESIS If you cover more than 30 reactions and need more space to continue, then you can just use a regular piece of paper to keep your list going. 1 3.2 MULTISTEP SYNTHESES To prepare yourself for solving multistep syntheses, you need to learn how to think in more than one move. It you carefully review your list of reactions. you will find that the products of some reactions are the starting material for other reactions. For example, you will find that some reactions are used to form double bonds, and other reactions add reagents across double bonds. So if you pair up all of the possibili- ties, you will create a list of many two—step syntheses. By studying these twovstep possibilities, you will begin to get familiar with seeing syntheses that are more than one step. Let’s see an example of what we mean. Below is one reaction that forms a double bond. It starts with an alkyne, and you will certainly learn this reaction at some point: H2 /=\ Lindlar’s catalyst Now consider one of the reactions where reagents react with a double bond: 0304 HO OH If we put these two reactions together into a two-step synthesis, we get the following: (1) H2/ Lindlar‘s catalyst HO OH (2) 0304 > H You should now get some practice with this. You will probably learn around five methods For making double bonds and probably around 10 reactions that involve reagents reacting with double bonds. If you put together all of the possibilities, you will find that there are around 50 possibilities, depending on exactly how many re— actions you leam. Clearly. you cannot keep a list like this as you go through the course. The list would be too long to study. And ifyort try to consider three-step syn- theses, you will find that the number ol‘ permutations is too large to even compile such a list. lt’sjust like our analogy to a game of chess. In chess, you cannot possibly memorize every possible orientation of all of the pieces and then memorize the best move for each of those possibilities. There are too many permutations. Instead, you learn how to analyze each situation and as time goes 13.3 RETROSYNTHETIC ANALYSIS 277 on you get better and better at it. By familiarizing yourself with certain permutations, yott will get better at figuring things out as you go along. So let’s start with the list that we talked about above—the approximately 50 possible two—step syntheses that involve forming a double bond and then doing something to that double bond. Again, you should not try to make a list like this throughout your entire course. This task would be impractical. But if you make this first list of roughly 50 synthe— ses, you will learn how to start thinking in more than one step. It is important for you to get accustomed to thinking this way. Take a separate sheet of paper and try to cre— ate this list using the reactions in the beginning of your course. If you do not get a chance to write down all 50 reactions. that‘s OK. As long as you begin the process and draw at least 10 or 20 of them, then you will start to understand what it is like to think in more than one step. After you have done this, we can start focusing on the main techniques for an— alyzing problems that display permutations that you have never seen. That is what the next section is all about. 1 3.3 RETROSYNTHETIC ANALYSIS When you see a synthesis problem for the first time. you are not expected to im— mediately know the answer. 1 cannot streSs this enough. It is so common for stu- dents to get overly anxious when they see synthesis problems that they cannot solve. Get used to it. This is the way it is supposed to be. Going back to our chess analogy, you don’t need to make a move as soon as it is your turn. You are allowed to think about it first. In fact, you are supposed to think about it first. So, how do you begin thinking about a multistep synthesis problem where you do not immedi— ately see the solution? The most powerful technique is called mtmsvntheric analy- sis. This means that you analyze the problem backward. Let’s see how this works with an example: The synthesis problem above is a multistep synthesis problem, because we do not have a single reaction that allows us to do this transformation in just one step. 50 the best way to start is to first look at the product and work our way backward. We see that the product is a dibromide. So we ask ourselves: Do we know any way of making a dibromide‘? You can see that to answer this question, you must have first mastered one-step syntheses. If you have not yet done this for all of the reac— tions that you have learned so far. you will need to go back to the beginning of this chapter and do that first (if you are a student in this situation. continue reading for now. so you can see where this is all going). 278 CHAPTER 13 SYNTHESIS So we should be able to recognize that we know how to make dibromides from double bonds. We draw the alkene that would have been used to form the product: WA ? Br Br Bfg Now we are one step Closer to solving this problem. The next step is to ask if there is a way to turn the starting material into this double bond. And there is. We just do an elimination reaction to get the double bond. 30 now we have solved our synthe» sis by working backward: %——+" Br Br Strong Base V Notice that the stereochemistry and regiochemistry needs to work out for every step. You cannot use a step that has the wrong stereochemistt‘y or regiochem» istry. I suppose you could have memorized all possible two'step syntheses from the reactions in your textbook, and then you would have gotten this problem right away (maybe . . .). but that is not a practical approach. What will you do for three-step or four-step syntheses? You need to get accustomed to thinking backward. The more practice you can get, the better ofl‘ you will be. Here is where we run into a big problem. There is no way for me to give you problems that are appropriate. Every course goes at its own pace, in its own order, and with exams at different points in the course. 1 cannot give problems that will be perfectly appropriate for every student everywhere. So, how are we going to get practice? Very simply. You are going to make your own problems. We see how to do this in the next section. 13.4 CREATING YOUR OWN PROBLEMS Creating your own problems is easier than it sounds. You just choose any reaction from the lists that you have been making (in Chapters 8. 12, and I3). Then look at 13.4 CREATING YOUR OWN PROBLEMS 279 the product of that reaction and choose another reaction that you have learned that will transform that compound into something else. We work backward to solve the synthesis problems. and we work forward to make up the problems. At each step, draw the product of that reaction and then move on to the next step. After you have gone two or three or four steps. erase everything in the middle. Just draw the very first compound and the final product. Draw an arrow between them, and you have a synthesis problem. There is one catch. You will not find that problem to be very challenging, be» cause you are the one who made it. So here is what you should do. Find a friend in the course, and each of you should make up 10 or 20 problems. Then you switch off with each other. You will find that this is a very effective method for studying. The larger your study group becomes. the more effective it will be. Don’t be shy. You will need to work with a friend to get the practice that you need. not to mention the valu» able peer support. If you are reading this book, then chances are that other students in your course have this book also. They will have the same need that you do. Team up with them. Even if you cannot find a friend with whom you can swap problems. it will still be a useful exercise to create your own problems. The process of creating prob- lems by itself is a worthwhile process. It will help you get accustomed to thinking in multiple steps for synthesis problems. To summarize, these are the keys to becoming proficient at solving synthesis problems: 1. Master the one—step syntheses by constant review. 2. Train yourself to work backward when solving a problem. 3. And, finally, get lots of practice. ...
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This note was uploaded on 07/31/2010 for the course CHEM 241 taught by Professor Burnett during the Fall '07 term at UVA.

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Chapter 13 - CHAPTER SYNTHESIS Synthesis is really just the...

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