How to do well on organic synthesis problems?

[wondergirl3]

I just miserably failed an orgo exam a couple hours ago and the main topics were carbonyls and organic synthesis. I studied and did practice problems, but the effort did not translate to the test. How do you do well on these synthesis problems? While studying, I had everything down in my head and was able to draw out some syntheses, but today on the test, I couldn't do the problems.

I am very good at mechanisms, but when it comes down to listing the reagents, products, and conditions for a possible synthesis, I just don't know what to do. How do I do well on syntheses problems? I practiced a lot, but still did badly.

Sincerely,
wondergirl3

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[Cyberdyne 101]

You should already have the synthesis of "representative products" and their intermediates mapped out prior to your exam. Also, it's often necessary to know various ways to synthesize a particular compound in case you run into barriers and/or you forget something while taking the exam.

 

[Cyberdyne 101]

What sort of synthesis problems were you dealing with? Did they involve Grignard reagents?

 

[Lucca]

If you truly know your mechanisms really well then synthesis should be no problem. My strategy for synthesis is:


1) count the carbons. How many carbons do I have in the reagent versus the product? If your problems are anything like mine youcan generally use as much of the reagent as possible but only that reagent for the carbons in the final product. Does the number of carbons in the product divide evenly between the number of carbons in the reagent? Yes ---> move on. No ---> Since you can't just make carbons out of thin air you are most likely going to employ a mechanism that somehow splits carbon carbon bonds. Ozonolysis, for example, where the final product is one of the two aldehydes/ketones could be one example. Generally the answer is Yes.

2) identify the last reaction that takes place in order to give the desired product. This is usually a nucleophillic addition or one of the alkene, alkyne bond reducing reactions.

3) once I have all the chunks that need to be added together (that is, reagent has 3 carbons, product has 9, that means 3 "chunks" and two separate nucleophillic additions) I just go ahead and throw all the mechanisms I know at the reagent to make the chunks.

4) look back through my intermediates and make sure I didnt miss any carbo cation rearrangements, methyl or hydrogen shifts, major or minor products, or racemic stereochemistries.

5) you're done!


The key is to be able to draw each mechanism cold and know precisely how every reaction takes place.

 

[spockprime]

The key that I found to doing well on synthesis problems was embracing retrosynthesis -- or working backwards. If you know all of your required reactions, then from there it is a matter of working backwards step by step, in what are essentially one step problems at that point.

So, you will have some starting substrate and they want you to show how to make a product. As someone has mentioned previously, count your carbons to determine whether or not you'll need to use some kind of reaction to add carbons. Also, make a note of what functional group transformation has occurred (say, going from an alcohol to an alkyne). Once you've set this groundwork, look at just the final product. Ask yourself, "How do I know how to make this?" For example, you have an alkyne in the end product... start thinking about the reaction(s) that you've learned that could get you to that product. Once you think of it, draw an arrow and write your reagents on the arrow and the structure that it had to have come from immediately prior to being treated with those reagents at the other end of the arrow. Keep repeating this process with the essential question ("How do I make this?") until you come to a point where you can connect one of your intermediate steps to the starting substrate. Then, read your synthesis forwards to make sure that it makes sense and that you've accounted for all the carbons or any stereochemistry, and then you're done!

This is definitely a very visual process and one that is more useful if explained with a problem. If you'd like, PM me and I'd be happy to help out. Also, I found that drawing out a reaction map with all the reactions and their respective reagents that I needed for my class to be extremely helpful. For example, it was a nice way to see all the ways to make an alkene, and then what I could make out of that alkene, and so on. It helped interconnect things very well.

 

[Pacna]

I recall that this was a thing at one time in my distant past.

 

[Cyberdyne 101]

This is going to sound ultra-geeky, but organic synthesis is loads of fun if you're approaching it properly. @Lucca and @spockprime provided excellent advice. You should definitely listen to their recommendations.

 

[AspiringERMD]

The key that I found to doing well on synthesis problems was embracing retrosynthesis -- or working backwards. If you know all of your required reactions, then from there it is a matter of working backwards step by step, in what are essentially one step problems at that point.

So, you will have some starting substrate and they want you to show how to make a product. As someone has mentioned previously, count your carbons to determine whether or not you'll need to use some kind of reaction to add carbons. Also, make a note of what functional group transformation has occurred (say, going from an alcohol to an alkyne). Once you've set this groundwork, look at just the final product. Ask yourself, "How do I know how to make this?" For example, you have an alkyne in the end product... start thinking about the reaction(s) that you've learned that could get you to that product. Once you think of it, draw an arrow and write your reagents on the arrow and the structure that it had to have come from immediately prior to being treated with those reagents at the other end of the arrow. Keep repeating this process with the essential question ("How do I make this?") until you come to a point where you can connect one of your intermediate steps to the starting substrate. Then, read your synthesis forwards to make sure that it makes sense and that you've accounted for all the carbons or any stereochemistry, and then you're done!

This is definitely a very visual process and one that is more useful if explained with a problem. If you'd like, PM me and I'd be happy to help out. Also, I found that drawing out a reaction map with all the reactions and their respective reagents that I needed for my class to be extremely helpful. For example, it was a nice way to see all the ways to make an alkene, and then what I could make out of that alkene, and so on. It helped interconnect things very well.

Beat me to it... working backward caused an immediate and enormous improvement in my ability to do synthesis problems. I was hopeless at them beforehand. Actually spent most of my Thanksgiving eating pie and working through syntheses with friends from class.

 

[spockprime]

This is going to sound ultra-geeky, but organic synthesis is loads of fun if you're approaching it properly. @Lucca and @spockprime provided excellent advice. You should definitely listen to their recommendations.

Oh my gosh YES isn't it great??! I know that I sound crazy to all of my friends when I talk about how fun synthesis problems can be, so it's cool to find someone else who appreciates them for what they are. They're just like little puzzles, but there is truly a very methodical way to approach them, with plenty of room for creativity along the way depending on how many reactions you've learned by that point. My friend sent me a cool synthesis from some grad textbook, and it must have taken 30 steps or something, it was frustrating and exhilarating at the same time.

Beat me to it... working backward caused an immediate and enormous improvement in my ability to do synthesis problems. I was hopeless at them beforehand. Actually spent most of my Thanksgiving eating pie and working through syntheses with friends from class.

Definitely, I'm convinced working backwards is the key. Once you get to organic II, there's just no way to see how to do things forwards sometimes, and it's just not worth the headache. Instead you can calmly (and confidently!) go through a problem step by step and just relax once you're done. Not to say it isn't hard sometimes (like when determining order of steps with a complex benzene chem synthesis), but overall it becomes very straightforward. Glad you found success with that method, too!

 

[mehc012]

Oh my gosh YES isn't it great??! I know that I sound crazy to all of my friends when I talk about how fun synthesis problems can be, so it's cool to find someone else who appreciates them for what they are. They're just like little puzzles, but there is truly a very methodical way to approach them, with plenty of room for creativity along the way depending on how many reactions you've learned by that point. My friend sent me a cool synthesis from some grad textbook, and it must have taken 30 steps or something, it was frustrating and exhilarating at the same time.



Definitely, I'm convinced working backwards is the key. Once you get to organic II, there's just no way to see how to do things forwards sometimes, and it's just not worth the headache. Instead you can calmly (and confidently!) go through a problem step by step and just relax once you're done. Not to say it isn't hard sometimes (like when determining order of steps with a complex benzene chem synthesis), but overall it becomes very straightforward. Glad you found success with that method, too!

Yup...it's also usually the 'official' method. Most of every problem set in my Synthetic Organic class was 'draw the retrosynthetic tree of...'
That includes a bunch of fun dead ends, too!

 

[Cyberdyne 101]

Oh my gosh YES isn't it great??! I know that I sound crazy to all of my friends when I talk about how fun synthesis problems can be, so it's cool to find someone else who appreciates them for what they are. They're just like little puzzles, but there is truly a very methodical way to approach them, with plenty of room for creativity along the way depending on how many reactions you've learned by that point. My friend sent me a cool synthesis from some grad textbook, and it must have taken 30 steps or something, it was frustrating and exhilarating at the same time.



Definitely, I'm convinced working backwards is the key. Once you get to organic II, there's just no way to see how to do things forwards sometimes, and it's just not worth the headache. Instead you can calmly (and confidently!) go through a problem step by step and just relax once you're done. Not to say it isn't hard sometimes (like when determining order of steps with a complex benzene chem synthesis), but overall it becomes very straightforward. Glad you found success with that method, too!

For one of my organic 2 exams I did a 4-5 step synthesis problem in 10 steps because I simply forgot how to synthesize one key intermediate

 

[67552931811]

As has been stated already, work backwards.

I loved Organic, and was very good at it, but I struggled at first with synthesis problems. You're not alone, OP. Keep working hard and don't stress. GL!

 

[aegistitan]

Haha, based on your post history you're definitely in my class. Anyway, the key to success is the Harvard exams and resources, here is a link.

http://isites.harvard.edu/icb/icb.do?keyword=k64740&pageid=icb.page290607

Anyway, our professor's exams aren't as hard as these so do them and you will be good. Our professor mainly has 3 step synthesis problems, I've seen Harvard go up to 6 step. Look at the functional group transformation quiz on the bottom. Fill that out on your own and you should be able to handle our professor's synthesis problems no sweat.

Anyway, if you're given a starting material, say for example bromobenzene , try to see how that starting material could possibly fit in the products. And like the others have said before me, you could work backwards. I find it helpful to identify what functional groups there are and write them on the paper, instead of thinking, "hmm... I have some type of ester.. how can I get there from bromobenzene..." think "Hmm.. I have an ester, what can I transform into an ester.." Also ask the other students in your class for help, make use of the facebook group!

Also the grade's not out yet, so let's hope the curve pulls through!

 

[wondergirl3]

Thanks everyone! I'll try working backwards for the next exam (which happens to be the final)

Haha, based on your post history you're definitely in my class. Anyway, the key to success is the Harvard exams and resources, here is a link.

http://isites.harvard.edu/icb/icb.do?keyword=k64740&pageid=icb.page290607

Anyway, our professor's exams aren't as hard as these so do them and you will be good. Our professor mainly has 3 step synthesis problems, I've seen Harvard go up to 6 step. Look at the functional group transformation quiz on the bottom. Fill that out on your own and you should be able to handle our professor's synthesis problems no sweat.

Anyway, if you're given a starting material, say for example bromobenzene , try to see how that starting material could possibly fit in the products. And like the others have said before me, you could work backwards. I find it helpful to identify what functional groups there are and write them on the paper, instead of thinking, "hmm... I have some type of ester.. how can I get there from bromobenzene..." think "Hmm.. I have an ester, what can I transform into an ester.." Also ask the other students in your class for help, make use of the facebook group!

Also the grade's not out yet, so let's hope the curve pulls through!

Wow! That transformation quiz is great! I had an earlier map from masteringorganicchemistry, but it didn't really have any of the stuff covered on this test. That bromobenzene one wasn't that big of the problem (just do the HME and blah blah). The fill in the missing stuff were impossible (to me)! I hope the curve is good!

 

[aegistitan]

Thanks everyone! I'll try working backwards for the next exam (which happens to be the final)



Wow! That transformation quiz is great! I had an earlier map from masteringorganicchemistry, but it didn't really have any of the stuff covered on this test. That bromobenzene one wasn't that big of the problem (just do the HME and blah blah). The fill in the missing stuff were impossible (to me)! I hope the curve is good!

Ah, those fill in the blank problems were mainly 1 step transformation problems. So it seems you're not having trouble with the synthesis problems, the people in this thread were giving you advice for approaching multi-step open ended synthesis problems. For the 1 step transformation problems you have a start point and an end point. So you can think, "Hmm I need to go from a tertiary amide to a tertiary amine, I'm essentially replacing the carbonyl group with two C-H bonds, what reagent can do that" the transformations quiz should help you on that for sure.

I would recommend you seek advice from people who take the class currently, or have in the past. The advice your receive on SDN, although good, is generalized, and advice specific to our class may benefit you more. If you want you can PM me if you want me to answer any specific questions.

 

[wondergirl3]

Ah, those fill in the blank problems were mainly 1 step transformation problems. So it seems you're not having trouble with the synthesis problems, the people in this thread were giving you advice for approaching multi-step open ended synthesis problems. For the 1 step transformation problems you have a start point and an end point. So you can think, "Hmm I need to go from a tertiary amide to a tertiary amine, I'm essentially replacing the carbonyl group with two C-H bonds, what reagent can do that" the transformations quiz should help you on that for sure.

I would recommend you seek advice from people who take the class currently, or have in the past. The advice your receive on SDN, although good, is generalized, and advice specific to our class may benefit you more. If you want you can PM me if you want me to answer any specific questions.

Yup, my friends have been telling me that the group helps too. But, the problem is that I don't have a Facebook account. My friends have been pressuring me to make one but I feel like that will distract me from my work. That's a whole different topic itself, haha.

But anyways, I will try to do what you said, and analyze the changes from reactants to products and then design probable paths. Thanks!

(P.S. Do you have the Harvard site link for Orgo 2? The one you posted seems very helpful, and it would be awesome if there was a similar page for Orgo 2. It's cool that Harvard used the same book as us, so it is very relatable.)