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Thursday, February 19, 2009
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Wednesday, October 29, 2008
Drawing isomers from a molecular formula
This is a very common problem type seen at the beginning of a course in organic chemistry, and as such they have a sneaky way making it onto exams. They are of the kind in which a question is asked such as, "Draw as many of the structural isomers of the formula CXHY as you can."
Here I describe a systematic technique for drawing the isomers for saturated hydrocarbons (the alkanes), which have the formula CNHN+2. First I'll describe the technique, handled in five steps, and then I'll apply it to a problem to show you how to put it to practical use.
THE FIVE STEPS FOR DRAWING ISOMERS:
1. Draw the main chain.
2. Draw the main chain minus 1 carbon, and add a methyl group to as many positions as possible. Never add the methyl groups to the end of the chain, and watch not to repeat structures (it's okay if you accidentally repeat structures, for they will be caught and discarded when you do step 5).
3. Draw the main chain minus 2 carbons, and add two one-carbon groups (two methyls) or one 2-carbon group (an ethyl) to as many positions possible, trying not to repeat structures.
4. Continue subtracting and adding groups in this fashion until you run out of carbons or doing so only results in repeated structures.
5. Give the IUPAC name to all the compounds you drew. If you accidentally drew the same one twice, they will have identical names, and you can cross one of them off.
Here I describe a systematic technique for drawing the isomers for saturated hydrocarbons (the alkanes), which have the formula CNHN+2. First I'll describe the technique, handled in five steps, and then I'll apply it to a problem to show you how to put it to practical use.
THE FIVE STEPS FOR DRAWING ISOMERS:
1. Draw the main chain.
2. Draw the main chain minus 1 carbon, and add a methyl group to as many positions as possible. Never add the methyl groups to the end of the chain, and watch not to repeat structures (it's okay if you accidentally repeat structures, for they will be caught and discarded when you do step 5).
3. Draw the main chain minus 2 carbons, and add two one-carbon groups (two methyls) or one 2-carbon group (an ethyl) to as many positions possible, trying not to repeat structures.
4. Continue subtracting and adding groups in this fashion until you run out of carbons or doing so only results in repeated structures.
5. Give the IUPAC name to all the compounds you drew. If you accidentally drew the same one twice, they will have identical names, and you can cross one of them off.
CHEMISTRY GUIDE
What is multistep synthesis?
Multistep synthesis is the process of taking a readily available compounds (ones you can buy) and converting them into desired products using known reactions. Multistep syntheses require more than one step, and so one or more intermediate compounds are formed along the way.
What are multistep synthesis problems
Typical multistep synthesis problems give a starting material and a product and instruct you to devise a route that takes the starting material into the product. For example, you might be asked to convert starting material W into product Z using reagents you've learned.
multistep synthesis question
What's an acceptable answer to these problems?
The way to answer these problems is to show the reagents that convert the starting material into the intermediate compounds, and, finally, into the product. For example, if you were asked to convert compound W into compound Z, you might convert W into an intermediate compound (X), which could in turn be reacted to form another intermediate compound (Y), which could be reacted once more to form the product (Z). Note that no mechanisms (arrow-pushing) are shown for the individual reaction steps, just the reagents and any intermediate compounds formed along the way.
multistep synthesis answer
Six tips for working through multistep synthesis problems:
Multistep syntheses problems can be very challenging. So here are six tips that can aid you in solving these types of problems.
1. Know the reactions.
This is the basic requirement. No matter how smart you are, you don't stand a chance on synthesis questions unless you know the reactions. Memorize the reagents, use flash cards, use whatever techniques you find most helpful, but get the reactions down cold. Since organic chemistry is a cumulative course, you can't afford to forget any reactions that have been previously covered, so never throw your stack of old flash cards away, but rather keep adding to the pile (the deck will be thick by the end of the course). Often, textbooks have end-of-chapter reaction summaries that can be helpful in making up flash cards.
2. Compare the carbon skeletons.
Compare the carbon skeleton of the starting material to the product. Were any carbons lost or added? If so, can you identify where they were added or lost? A carbon count of the reactant and the product doesn't take long, but can help you determine what kind of reactions you are dealing with.
Take the following simple example. The red portion of the molecule identifies where the likely carbon skeleton of the reactant is found in the product. Doing this allows you to clearly see what portion needs to be added or lost during your synthesis (it may seem trivial in this obvious example, but it can be a quite helpful to organize your thoughts in tougher problems).
3. Work backwards
Ever find it easier to get through a maze starting at the finish and working back to the start? The same thing applies to multistep synthesis (working backwards like this is a technique termed retrosynthesis). Look at your product, and think of all the reactions that you know of that could form it, ignoring your starting material.
If your product is an alkene, think potentially of alkene-forming reactions like elimination reactions or the Wittig reaction. Write all these reactions out and look what reactant would be required for each. Now look at your starting material. The reaction that most resembles your starting material is probably the best one to select as a potential candidate.
For example, if you were asked to do the following synthesis:
After completing the first two steps above, you would want to think of ways to make the alkene in the product. Ignore the starting material for the moment. Just brainstorm all the ways you can think of to make the alkene and write them down on your scratch paper. You should get something that looks like this:
Now you have three possible routes to choose from. The route to choose is the one that uses a reactant that most resembles our original starting material. If you did step 2 (accounting for the carbon skeleton), you would know that the product has one carbon more than the starting material. Only the first reaction, the Wittig reaction, accounts for this additional carbon, and since the reactant for the Wittig reaction most resembles our starting material, this would be the reaction to tentatively choose. If it turns out to be wrong, we can always go back and try another route.
Looking at our reaction scheme, we now have something that looks like this:
Now repeat the same procedure for cyclohexanone, thinking of all the different ways you could make the ketone. One pointer here is that the closer you get to completing a retrosynthesis, the more you can reference the starting material in your thinking. At this point, for example, you may want to tune your thinking from "I need to think of all the ways I can make cyclohexanone" to perhaps something more on the lines of "I need a reaction that converts an alcohol to a ketone". If you did step one, you would know several ways (different chromate reagents, KMNO4, Ag2O, etc).
If you get stuck, go back and try one of the other pathways. If the Wittig reaction in our example had let to a dead end, then we could have gone back and tried one of the elimination reactions. Choosing the correct way back is often a manner of feel, and that only comes after working a lot of problems (See tip 5).
4. Making your life easier: Sorting your synthetic tools
There are pretty much two types of synthetic tools available to you: (1) carbon-carbon bond forming reactions, and (2) functional group reactions that convert one functional group into another (like a reaction that converts an alcohol into a ketone, for example).
You may have noticed that many, many multistep syntheses involve making carbon-carbon bonds (which, in turn, you will have noticed by comparing the carbon skeleton of the starting material and product as suggested in a previous tip). In the toolbox of all your reactions, these carbon-carbon bond forming reactions should go right on the top where they are easy to reach. The functional group transformations are of more secondary importance and go on the bottom of the toolbox to be dusted off when needed.
synthetic toolbox
Synthetic toolbox.
Step 1: Compiling a list of all the carbon-carbon forming reactions you've learned.
Carbon-carbon reactions are your primary tools to build up your molecules, and are perhaps the most important and valuable reactions to remember. Once you know which carbon-carbon reactions to use to make the product, the other reactions often seem to magically fall into place.
At first, your list of carbon-carbon forming reactions will be small. But this list will get bigger. At the end of your first semester, you may have a list that contains some of the following carbon-carbon reactions (and perhaps others, depending on what material your professor and textbook chooses to cover):
Your most important synthetic tools: Carbon-carbon forming reactions
* Acetylide reactions. These reactions involve use of an acetylide (a deprotonated terminal alkyne) as a nucleophile. Typically, the acetylide is used to attack a primary halide (in an SN2 reaction) or a carbonyl group to make an alcohol.
acetylide chemistry
* Cyanide additions to primary halides. Cyanides can be substituted for halides in a SN2 or SN1 substitution reaction (although I'd recommend you stick with SN2 reactions rather than SN1 reactions in your multistep syntheses).
cyano addition
* The Wittig Reaction. Makes a carbon-carbon double bond starting with a carbonyl compound phosphonium ylide
wittig
* Friedel-Crafts reactions (for aromatic rings). This reaction makes an aromatic-carbon bond.
* Diels-Alder reaction. This reaction takes a diene and a dienophile to make ringed and bicyclic products. This reaction makes two new carbon-carbon bonds.
Diels-Alder reaction
* Grignard reaction. This reaction adds a halomagnesium reagent (Grignard reagent) to a carbonyl to make an alcohol.
Grignard reaction
Some common carbon-carbon forming reactions in first-semester undergraduate organic chemistry
Later (second semester typically), you may add enolate and enol reactions to the list (like the aldol reaction, Claisen reaction, Michael reaction, etc).
Tip 4 continued... Adding carbon-carbon forming reactions into your retrosyntheses
All right. You've learned your reactions and organized them into (at least) two categories: functional group conversions and carbon-carbon bond forming reactions. You've got a fresh synthetic problem in front of you. So now what?
Now you want to think of which carbon-carbon bonds you have to form to take the starting material into the product.
Take an example synthesis:
In this example, you can think, "well, if I'm starting with cyclohexane, the carbon-carbon bond I'm going to have to make connects the cyclohexane ring to the chain containing the carbonyl (C=O) group."
Then you can think "which of the carbon-carbon forming reactions would be useful to make this carbon-carbon bond?" Then check off the list to see which ones might be used and which can be eliminated from consideration.
* Acetylide chemistry: This reaction won't work to make this bond. Acetylide reactions work well only with primary halides. The acetylide chain would have to attack a ring carbon which would be a secondary carbon. Also, it's not clear how to selectively take the resulting alkyne to the ketone since it would be an internal alkyne.
* Cyanide addition: This won't work. Cyanides add only one carbon. You need to add three carbons.
* Wittig reaction: This one might work. Of course, Wittig reactions form a carbon-carbon double bond and you want a carbon-carbon single bond. Probably it's best to see if there's a better route to go before trying this one.
* Friedel-Crafts: You don't have an aromatic ring in this problem, so this reaction's out of the question.
* Diels-Alder reaction. This won't work. The Diels-Alder reaction forms rings and bicyclic compounds. You already have the ring in the starting material.
* Grignard reagents. This reaction should work. Of course, a Grignard reagent reacts with a carbonyl compound to make an alcohol, not a ketone. Fortunately, since you've learned all of your functional group transformations, you know that it's a straightforward task to take a secondary alcohol into a ketone. This reaction looks the most promising so try this carbon-carbon bond forming reaction.
Now that you've chosen the carbon-carbon forming reaction, notice how all the other functional group conversions required to complete the synthesis seem to fall neatly into place. It's usually best to work backwards (using the retrosynthesis approach I discussed in a previous tip), so do that for this problem.
Since you know the carbon-carbon bond-forming reaction forms an alcohol, the last step must convert that alcohol to the ketone in the product. In this case, a number of oxidizing reagents could be used. PCC or Jones' reagent would work just fine here. (You could use other chromium reagents as well)
To make this alcohol you use the Grignard reagent in the carbon-carbon bond-making step that you decided upon earlier. To make a secondary alcohol, you must react the Grignard reagent with an aldehyde. I chose cyclohexyl magnesium chloride here as the starting material, but you could just as easily have gone with cyclohexyl magnesium bromide (either works fine)
To make Grignard reagents you add magnesium turnings to an alkyl halide. Since I chose in the previous reaction to make a chloride Grignard reagent, the starting material I choose in this case is chlorocyclohexane (it would be bromocyclohexane if you went with the bromo Grignard reagent).
The way to add a chlorine to an alkane is to chlorinate using free-radical chemistry in the presence of light.
And that's the retrosynthesis for this molecule. Notice how the steps all seemed to be logical once the carbon-carbon bond forming reaction was chosen.
5. Check your answer.
Once you have a potential synthesis, go back and make sure all of your reagents are compatible with the functional groups on your molecule. Make sure, for example, if you are proposing a Grignard reaction, that there are no alcohols or other incompatible functionalities on your reagent. Undergraduate organic professors often seem to take delight in creating challenging (read: tricky) exam questions, giving little partial credit for incorrect answers, so double check every detail of your synthesis for correctness. Which leads us to the most important tip at becoming good at multistep synthesis questions, which is:
6. Work lots of problems.
There's no way around it, no magic formula. A good textbook will have plenty of problems to practice on. Start with easy synthesis problems to get the feel of what is required, then work your way to harder problems. Get help from a tutor if you need it. If you have a solutions manual to your text, don't refer to it until after you have completed the problem. Looking at the solution manual and thinking "yeah, I could do this problem," or "yeah, that looks about right," is no substitute for actually doing it. On an exam, the question will never be "Does this look right to you, check yes or no." So you'll need experience to get the feel of how to work problems. Get lots of experience. Working in groups can help, but make sure that you do the work yourself. Don't let someone else do it for you. You're on your own when exam time comes.
Multistep synthesis is the process of taking a readily available compounds (ones you can buy) and converting them into desired products using known reactions. Multistep syntheses require more than one step, and so one or more intermediate compounds are formed along the way.
What are multistep synthesis problems
Typical multistep synthesis problems give a starting material and a product and instruct you to devise a route that takes the starting material into the product. For example, you might be asked to convert starting material W into product Z using reagents you've learned.
multistep synthesis question
What's an acceptable answer to these problems?
The way to answer these problems is to show the reagents that convert the starting material into the intermediate compounds, and, finally, into the product. For example, if you were asked to convert compound W into compound Z, you might convert W into an intermediate compound (X), which could in turn be reacted to form another intermediate compound (Y), which could be reacted once more to form the product (Z). Note that no mechanisms (arrow-pushing) are shown for the individual reaction steps, just the reagents and any intermediate compounds formed along the way.
multistep synthesis answer
Six tips for working through multistep synthesis problems:
Multistep syntheses problems can be very challenging. So here are six tips that can aid you in solving these types of problems.
1. Know the reactions.
This is the basic requirement. No matter how smart you are, you don't stand a chance on synthesis questions unless you know the reactions. Memorize the reagents, use flash cards, use whatever techniques you find most helpful, but get the reactions down cold. Since organic chemistry is a cumulative course, you can't afford to forget any reactions that have been previously covered, so never throw your stack of old flash cards away, but rather keep adding to the pile (the deck will be thick by the end of the course). Often, textbooks have end-of-chapter reaction summaries that can be helpful in making up flash cards.
2. Compare the carbon skeletons.
Compare the carbon skeleton of the starting material to the product. Were any carbons lost or added? If so, can you identify where they were added or lost? A carbon count of the reactant and the product doesn't take long, but can help you determine what kind of reactions you are dealing with.
Take the following simple example. The red portion of the molecule identifies where the likely carbon skeleton of the reactant is found in the product. Doing this allows you to clearly see what portion needs to be added or lost during your synthesis (it may seem trivial in this obvious example, but it can be a quite helpful to organize your thoughts in tougher problems).
3. Work backwards
Ever find it easier to get through a maze starting at the finish and working back to the start? The same thing applies to multistep synthesis (working backwards like this is a technique termed retrosynthesis). Look at your product, and think of all the reactions that you know of that could form it, ignoring your starting material.
If your product is an alkene, think potentially of alkene-forming reactions like elimination reactions or the Wittig reaction. Write all these reactions out and look what reactant would be required for each. Now look at your starting material. The reaction that most resembles your starting material is probably the best one to select as a potential candidate.
For example, if you were asked to do the following synthesis:
After completing the first two steps above, you would want to think of ways to make the alkene in the product. Ignore the starting material for the moment. Just brainstorm all the ways you can think of to make the alkene and write them down on your scratch paper. You should get something that looks like this:
Now you have three possible routes to choose from. The route to choose is the one that uses a reactant that most resembles our original starting material. If you did step 2 (accounting for the carbon skeleton), you would know that the product has one carbon more than the starting material. Only the first reaction, the Wittig reaction, accounts for this additional carbon, and since the reactant for the Wittig reaction most resembles our starting material, this would be the reaction to tentatively choose. If it turns out to be wrong, we can always go back and try another route.
Looking at our reaction scheme, we now have something that looks like this:
Now repeat the same procedure for cyclohexanone, thinking of all the different ways you could make the ketone. One pointer here is that the closer you get to completing a retrosynthesis, the more you can reference the starting material in your thinking. At this point, for example, you may want to tune your thinking from "I need to think of all the ways I can make cyclohexanone" to perhaps something more on the lines of "I need a reaction that converts an alcohol to a ketone". If you did step one, you would know several ways (different chromate reagents, KMNO4, Ag2O, etc).
If you get stuck, go back and try one of the other pathways. If the Wittig reaction in our example had let to a dead end, then we could have gone back and tried one of the elimination reactions. Choosing the correct way back is often a manner of feel, and that only comes after working a lot of problems (See tip 5).
4. Making your life easier: Sorting your synthetic tools
There are pretty much two types of synthetic tools available to you: (1) carbon-carbon bond forming reactions, and (2) functional group reactions that convert one functional group into another (like a reaction that converts an alcohol into a ketone, for example).
You may have noticed that many, many multistep syntheses involve making carbon-carbon bonds (which, in turn, you will have noticed by comparing the carbon skeleton of the starting material and product as suggested in a previous tip). In the toolbox of all your reactions, these carbon-carbon bond forming reactions should go right on the top where they are easy to reach. The functional group transformations are of more secondary importance and go on the bottom of the toolbox to be dusted off when needed.
synthetic toolbox
Synthetic toolbox.
Step 1: Compiling a list of all the carbon-carbon forming reactions you've learned.
Carbon-carbon reactions are your primary tools to build up your molecules, and are perhaps the most important and valuable reactions to remember. Once you know which carbon-carbon reactions to use to make the product, the other reactions often seem to magically fall into place.
At first, your list of carbon-carbon forming reactions will be small. But this list will get bigger. At the end of your first semester, you may have a list that contains some of the following carbon-carbon reactions (and perhaps others, depending on what material your professor and textbook chooses to cover):
Your most important synthetic tools: Carbon-carbon forming reactions
* Acetylide reactions. These reactions involve use of an acetylide (a deprotonated terminal alkyne) as a nucleophile. Typically, the acetylide is used to attack a primary halide (in an SN2 reaction) or a carbonyl group to make an alcohol.
acetylide chemistry
* Cyanide additions to primary halides. Cyanides can be substituted for halides in a SN2 or SN1 substitution reaction (although I'd recommend you stick with SN2 reactions rather than SN1 reactions in your multistep syntheses).
cyano addition
* The Wittig Reaction. Makes a carbon-carbon double bond starting with a carbonyl compound phosphonium ylide
wittig
* Friedel-Crafts reactions (for aromatic rings). This reaction makes an aromatic-carbon bond.
* Diels-Alder reaction. This reaction takes a diene and a dienophile to make ringed and bicyclic products. This reaction makes two new carbon-carbon bonds.
Diels-Alder reaction
* Grignard reaction. This reaction adds a halomagnesium reagent (Grignard reagent) to a carbonyl to make an alcohol.
Grignard reaction
Some common carbon-carbon forming reactions in first-semester undergraduate organic chemistry
Later (second semester typically), you may add enolate and enol reactions to the list (like the aldol reaction, Claisen reaction, Michael reaction, etc).
Tip 4 continued... Adding carbon-carbon forming reactions into your retrosyntheses
All right. You've learned your reactions and organized them into (at least) two categories: functional group conversions and carbon-carbon bond forming reactions. You've got a fresh synthetic problem in front of you. So now what?
Now you want to think of which carbon-carbon bonds you have to form to take the starting material into the product.
Take an example synthesis:
In this example, you can think, "well, if I'm starting with cyclohexane, the carbon-carbon bond I'm going to have to make connects the cyclohexane ring to the chain containing the carbonyl (C=O) group."
Then you can think "which of the carbon-carbon forming reactions would be useful to make this carbon-carbon bond?" Then check off the list to see which ones might be used and which can be eliminated from consideration.
* Acetylide chemistry: This reaction won't work to make this bond. Acetylide reactions work well only with primary halides. The acetylide chain would have to attack a ring carbon which would be a secondary carbon. Also, it's not clear how to selectively take the resulting alkyne to the ketone since it would be an internal alkyne.
* Cyanide addition: This won't work. Cyanides add only one carbon. You need to add three carbons.
* Wittig reaction: This one might work. Of course, Wittig reactions form a carbon-carbon double bond and you want a carbon-carbon single bond. Probably it's best to see if there's a better route to go before trying this one.
* Friedel-Crafts: You don't have an aromatic ring in this problem, so this reaction's out of the question.
* Diels-Alder reaction. This won't work. The Diels-Alder reaction forms rings and bicyclic compounds. You already have the ring in the starting material.
* Grignard reagents. This reaction should work. Of course, a Grignard reagent reacts with a carbonyl compound to make an alcohol, not a ketone. Fortunately, since you've learned all of your functional group transformations, you know that it's a straightforward task to take a secondary alcohol into a ketone. This reaction looks the most promising so try this carbon-carbon bond forming reaction.
Now that you've chosen the carbon-carbon forming reaction, notice how all the other functional group conversions required to complete the synthesis seem to fall neatly into place. It's usually best to work backwards (using the retrosynthesis approach I discussed in a previous tip), so do that for this problem.
Since you know the carbon-carbon bond-forming reaction forms an alcohol, the last step must convert that alcohol to the ketone in the product. In this case, a number of oxidizing reagents could be used. PCC or Jones' reagent would work just fine here. (You could use other chromium reagents as well)
To make this alcohol you use the Grignard reagent in the carbon-carbon bond-making step that you decided upon earlier. To make a secondary alcohol, you must react the Grignard reagent with an aldehyde. I chose cyclohexyl magnesium chloride here as the starting material, but you could just as easily have gone with cyclohexyl magnesium bromide (either works fine)
To make Grignard reagents you add magnesium turnings to an alkyl halide. Since I chose in the previous reaction to make a chloride Grignard reagent, the starting material I choose in this case is chlorocyclohexane (it would be bromocyclohexane if you went with the bromo Grignard reagent).
The way to add a chlorine to an alkane is to chlorinate using free-radical chemistry in the presence of light.
And that's the retrosynthesis for this molecule. Notice how the steps all seemed to be logical once the carbon-carbon bond forming reaction was chosen.
5. Check your answer.
Once you have a potential synthesis, go back and make sure all of your reagents are compatible with the functional groups on your molecule. Make sure, for example, if you are proposing a Grignard reaction, that there are no alcohols or other incompatible functionalities on your reagent. Undergraduate organic professors often seem to take delight in creating challenging (read: tricky) exam questions, giving little partial credit for incorrect answers, so double check every detail of your synthesis for correctness. Which leads us to the most important tip at becoming good at multistep synthesis questions, which is:
6. Work lots of problems.
There's no way around it, no magic formula. A good textbook will have plenty of problems to practice on. Start with easy synthesis problems to get the feel of what is required, then work your way to harder problems. Get help from a tutor if you need it. If you have a solutions manual to your text, don't refer to it until after you have completed the problem. Looking at the solution manual and thinking "yeah, I could do this problem," or "yeah, that looks about right," is no substitute for actually doing it. On an exam, the question will never be "Does this look right to you, check yes or no." So you'll need experience to get the feel of how to work problems. Get lots of experience. Working in groups can help, but make sure that you do the work yourself. Don't let someone else do it for you. You're on your own when exam time comes.
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