{"id":129,"date":"2018-11-21T14:20:49","date_gmt":"2018-11-21T14:20:49","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/?post_type=chapter&p=129"},"modified":"2022-02-14T03:43:16","modified_gmt":"2022-02-14T03:43:16","slug":"11-2-planning-a-synthesis","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/11-2-planning-a-synthesis\/","title":{"raw":"11.2. Planning a synthesis","rendered":"11.2. Planning a synthesis"},"content":{"raw":"Let's assume you want to make a particular product.\u00a0 In real life, you could choose from any commercially available starting material.\u00a0 However, when you're first learning how to make chemicals, that makes the problem far too open-ended, so usually students are given suitable starting materials.\u00a0 But even this simplified type of synthesis can seem overwhelming unless certain principles are followed, and these will be covered next:\r\n

Retrosynthesis<\/h3>\r\nFirst, do not<\/strong><\/span> just try random reactions of the starting material and see where they go.\u00a0 That can work for a one or maybe two-step synthesis, but if you try it on a longer problem it will end in tears!\u00a0 It is certainly useful to consider what you can make in one step from the starting material, but that probably won't give you the main part of the synthesis.\u00a0 Rather, you should look at the target product and work backwards from there - a method known as retrosynthesis.\u00a0 In other words, you should look at the product and say: \"How could I make that?\".\r\n\r\nThe reason retrosynthesis works is because usually a target product is more complex than the reactant(s) used to build it.\u00a0 Consider if you wanted to build a car, from these car parts:\"\"\r\n\r\nIf you just start putting random pieces together, you will soon become frustrated, as you attach a steering wheel to a starter motor, or insert a windshield wiper onto a seat belt.\u00a0 There are just too many options, and most of them are wrong.\u00a0 Instead, you need to look at the finished car, and try to work back from there; now you can see that the steering wheel needs to be attached to the steering column, in front of the driver's seat.\r\n\r\n\"\"\r\n\r\nIn the same way, it's much easier to plan the synthesis if you focus on how the target product is put together.\u00a0 Now we can start to work on the details of the synthesis.\r\n

Step 1: Mapping starting materials onto the product<\/h3>\r\nSince you will normally be given a starting material, and you should begin by comparing its \"skeleton\" with that of the product.\u00a0 By skeleton, we mean the main carbon framework and any rings - especially aromatic rings - without worrying too much about the functional groups like -OH that hang off the skeleton.\u00a0 (This is because the skeleton, once made, is very hard to change, whereas the functional groups are easy to alter.\r\n\r\nIt's very useful to number the carbons to keep track.\u00a0 This numbering can use whatever system you like, so don't worry about complying with IUPAC rules - it's just so you can see which carbon of the starting material ends up as which carbon in the product.\u00a0 Do we need to use the same molecule twice in the same synthesis?\u00a0 If so, you can number the carbons on the second molecule as 1', 2', etc..\u00a0 If you have a large group like a phenyl (Ph) ring that doesn't change, we don't need to count those carbons, we can just treat the Ph as a substituent group.\r\n\r\nOnce you can see ways to map the starting material onto the product skeleton, you should look more closely and map the functional group positions<\/em><\/strong> too. Don't worry that the starting material has an alkene and the product has a ether - it's just the positions of the functional groups that matter.\u00a0 You can treat alkenes and alkynes as functional groups that are on two neighboring carbons.\u00a0 In the example given, the new -OCH3<\/sub> (ether) functional group is going on carbon 2, in the place of the old alkene group on carbons 1-2.\u00a0 It is always much easier to introduce a connection or functional group at a position with existing functionality there (or at least nearby).\r\n\r\nLet's look at a simple example synthesis problem.\r\n\r\nExample problem 1: Synthesize the product shown, starting from 1-methylcyclohexene.\u00a0 You must use the starting material at least once, and you may use any viable reagent that delivers no more than two carbons.<\/em><\/strong>\r\n\r\n\"Question:\r\n\r\nIn this case, the six-carbon ring and the methyl group clearly make up most of the target structure; we simply need to add an ethoxy group across the double bond so it ends up trans<\/em> to the methyl group, on the neighboring carbon.\u00a0 Easier said than done - there is no single step reaction that will do all that.\u00a0 So we will need to design a multistep synthesis.\u00a0 In exam or homework problems there are often constraints put on the synthesis, such as.\u00a0 Here is the initial mapping, including the numbering of the carbons of the starting material skeleton:\r\n\r\n\"Mapping\r\n

Step 2: Identify key bonds to be made<\/h3>\r\nOnce you know how the starting material maps onto the product, it should be obvious which new bonds need to be made in order to assemble the new skeleton.\u00a0 These new bonds can be divided into two types:\r\n\r\n(a) Key bonds (aka<\/em> bonds which can't easily be unmade).\u00a0 These include almost all new C-C bonds<\/strong>, as well as any new rings<\/strong> that are made (rare in this class).\u00a0 It also includes new C-N amine bonds<\/strong> or C-O ether bonds<\/strong>.\u00a0 We need to identify these early in our planning.\r\n\r\n(b) Bonds to interchangeable functional groups (aka<\/em> bonds that are easily changed), or C-H bonds that are next to functional groups.\u00a0 We don't need to worry about these until the end of the planning process.\r\n\r\nFor our example synthesis, the key bond we need to make is the C-O ether bond from carbon 2, to add the new ethoxy group.\u00a0 Notice that we also need to make a new C-H bond at carbon 1, cis<\/em> to the new ethoxy group; that's less obvious because the skeletal structure doesn't show it explicitly.\u00a0 Although it's less important than the new C-O bond, we mustn't forget that we have to make that bond too. So, our synthesis must include an addition step as a key step.\r\n\r\nIf we can add the ethoxy group in one step - say by using CH3<\/sub>CH2<\/sub>OH (ethanol) - then we would only have one key bond to make.\u00a0 However, there is no method that adds an -OR group at the anti-Markovnikov<\/em> position; that means we will need to make the other ether C-O bond, from the ethyl group to the oxygen.\u00a0 So our key bonds to make are likely to be the two new C-O bonds<\/strong>.\r\n

Step 3: Consider how to make the key bond(s)<\/h3>\r\nThis is the key to solving the puzzle of the synthesis; once we've worked out how to make the key bond(s), the rest of the synthesis should fall into place (at least, it will with practice).\r\n\r\nThe problem here is that we're trying to do an anti-Markovnikov<\/em> addition to an alkene, and we only know a couple of ways to do that.\u00a0 Do any of them make a new C-O bond?\u00a0 We also want to keep in mind that we need to make a new C-H bond cis to the new C-O bond.\u00a0 (We will also need to make another C-O bond to the ethyl.).\r\n\r\nPlease now review section 10.7.5. on the page for section 10.7., Addition involving cyclic intermediates<\/a> (you will need to scroll past halfway down the page).\u00a0 This is the only<\/strong><\/em> reaction you've learnt so far that adds across a double bond to place the functional group at the anti-Markovnikov<\/em> position.\u00a0 So that's your only<\/strong><\/em> choice for the key addition step in the synthesis.\u00a0 What happens if we use this reaction with the starting material we're given?\r\n\r\n\"Hydroboration-oxidation\r\n\r\nThis looks very promising!\u00a0 (Just as well, since it's our only option for an addition reaction!)\u00a0 We have made one of the necessary C-O bonds at the correct position, and as a bonus we also added the new C-H bond cis<\/em> to the C-O. We're well on our way with this reaction!\r\n\r\nThat means we only have one key bond left to make - the other C-O bond.\u00a0 We need a way to convert an alcohol R-OH into an ether R-O-R'.\u00a0 Recall from section 9.5<\/a> that the most common way to make an ether is via the Williamson ether synthesis.\u00a0 This is an SN<\/sub>2 reaction between the conjugate base of an alcohol (an alkoxide) R-O-<\/sup>, and an alkyl halide R'-X, to give the ether R-O-R'.\u00a0 Since we already have the alcohol ROH, this is perfect for our needs - we just need to convert our alcohol into its conjugate base, then add the alkyl halide and we're done!\u00a0 In section 9.5, you learnt that NaH can be used to convert an alcohol into its conjugate base, the alkoxide.\u00a0 Let's see how that would work in our specific example synthesis:\r\n\r\n \r\n\r\n\"Williamson\r\n\r\nThis completes our synthesis!\u00a0 Note that if the starting alcohol is racemic, the other two structures will also be racemic.\u00a0 If you're unsure about stereochemistry of reactions, review section 4.5<\/a>.\r\n

Step 4. Adjust functional groups<\/h3>\r\nThese are reactions where we take the functional groups we made in our key steps, and convert them to the functional groups we need in our product.\r\n\r\nIn the example we just examined, we didn't need to do any additional changes to the functional groups to get to the product.\u00a0 In many synthesis problem these additional steps will be needed.\u00a0 Some examples of these functional group conversions are shown in this reaction map:\r\n\r\n\"A\r\n

Step 5: Write out the whole synthesis and check it carefully<\/h3>\r\nOnce you have written out all the steps, including any functional group changes, you should carefully check your synthesis:\r\n\r\n(a) Count your carbons<\/strong>!\u00a0 It's easy to make a mistake in a long synthesis, so you perhaps end up with ten carbons instead of the nine you need.\u00a0 Check that you're making the right product!\r\n\r\n(b) Synthetic traps<\/strong>.\u00a0 Common examples include incompatibilities (e.g., something that would prevent the reaction you want) or competing functional groups (e.g., another group that might also reaction).\u00a0 These types of problems are often not obvious when you're looking at individual steps, and you only see them when you see the overall synthesis.\r\n\r\n(c) Better way?<\/strong> Now you've gone through the whole sequence, look again at the \"big picture\" to see if there is a better way to do the synthesis.\u00a0 Sometimes a different approach will emerge at this time as you reflect on what you've done, and sometimes it may be better than your original.\r\n\r\nOur example synthesis problem was this:\r\n\r\n\"Question:\r\n\r\nAnd your answer should normally be written out like this\r\n\r\n\"Completed\r\n\r\nIn this case, our proposed synthesis is reasonably efficient and it doesn't have any incompatibilities.\u00a0 It matches with the problem asked at the beginning, and has the correct number of carbons.\u00a0 We have completed the synthesis!\r\n\r\nWith synthesis problems, you will find that they become much easier with practice.\u00a0 It is well known that our brains learn to solve complex problems by \"chunking\" - the way we chunk together letters to make common words and we read the whole word as one concept.\u00a0 The same applies in synthesis, where you will begin to see recognize common patterns, and you may well develop your own favorite reaction sequences. In the next section, I will list a few of my favorite sequences involving the chemistry from chapters 1-10.\r\n\r\nOne former student of mine told me that by studying synthesis problems he found that his chess game had improved; he learnt to work back from a desired \"checkmate\" and trace the possible ways to get there.\u00a0 You will need to memorize many different synthetic reactions and the reagents they use, but as you apply them in synthesis problems they will begin to have meaning.\u00a0 Before you can play chess, you need to learn the moves, but it only becomes meaningful (and fun!) once you start using those moves in a real game. In this way the reagents and conditions become much easier to remember.\r\n\r\nAs you get further in this course and learn more reactions, you will begin to see that (just as in chess) there are multiple correct ways to complete a synthesis - maybe hundreds, for a complex target product.\u00a0 However, there are also millions of wrong ways...!\r\n\r\nThis video<\/a> from Organic Chemistry Tutor is quite advanced at this point, but may give you a flavor of how a synthesis is put together.\r\n\r\nhttps:\/\/youtu.be\/I85LgmfkJ0o\r\n\r\n\"\"","rendered":"

Let’s assume you want to make a particular product.\u00a0 In real life, you could choose from any commercially available starting material.\u00a0 However, when you’re first learning how to make chemicals, that makes the problem far too open-ended, so usually students are given suitable starting materials.\u00a0 But even this simplified type of synthesis can seem overwhelming unless certain principles are followed, and these will be covered next:<\/p>\n

Retrosynthesis<\/h3>\n

First, do not<\/strong><\/span> just try random reactions of the starting material and see where they go.\u00a0 That can work for a one or maybe two-step synthesis, but if you try it on a longer problem it will end in tears!\u00a0 It is certainly useful to consider what you can make in one step from the starting material, but that probably won’t give you the main part of the synthesis.\u00a0 Rather, you should look at the target product and work backwards from there – a method known as retrosynthesis.\u00a0 In other words, you should look at the product and say: “How could I make that?”.<\/p>\n

The reason retrosynthesis works is because usually a target product is more complex than the reactant(s) used to build it.\u00a0 Consider if you wanted to build a car, from these car parts:\"\"<\/p>\n

If you just start putting random pieces together, you will soon become frustrated, as you attach a steering wheel to a starter motor, or insert a windshield wiper onto a seat belt.\u00a0 There are just too many options, and most of them are wrong.\u00a0 Instead, you need to look at the finished car, and try to work back from there; now you can see that the steering wheel needs to be attached to the steering column, in front of the driver’s seat.<\/p>\n

\"\"<\/p>\n

In the same way, it’s much easier to plan the synthesis if you focus on how the target product is put together.\u00a0 Now we can start to work on the details of the synthesis.<\/p>\n

Step 1: Mapping starting materials onto the product<\/h3>\n

Since you will normally be given a starting material, and you should begin by comparing its “skeleton” with that of the product.\u00a0 By skeleton, we mean the main carbon framework and any rings – especially aromatic rings – without worrying too much about the functional groups like -OH that hang off the skeleton.\u00a0 (This is because the skeleton, once made, is very hard to change, whereas the functional groups are easy to alter.<\/p>\n

It’s very useful to number the carbons to keep track.\u00a0 This numbering can use whatever system you like, so don’t worry about complying with IUPAC rules – it’s just so you can see which carbon of the starting material ends up as which carbon in the product.\u00a0 Do we need to use the same molecule twice in the same synthesis?\u00a0 If so, you can number the carbons on the second molecule as 1′, 2′, etc..\u00a0 If you have a large group like a phenyl (Ph) ring that doesn’t change, we don’t need to count those carbons, we can just treat the Ph as a substituent group.<\/p>\n

Once you can see ways to map the starting material onto the product skeleton, you should look more closely and map the functional group positions<\/em><\/strong> too. Don’t worry that the starting material has an alkene and the product has a ether – it’s just the positions of the functional groups that matter.\u00a0 You can treat alkenes and alkynes as functional groups that are on two neighboring carbons.\u00a0 In the example given, the new -OCH3<\/sub> (ether) functional group is going on carbon 2, in the place of the old alkene group on carbons 1-2.\u00a0 It is always much easier to introduce a connection or functional group at a position with existing functionality there (or at least nearby).<\/p>\n

Let’s look at a simple example synthesis problem.<\/p>\n

Example problem 1: Synthesize the product shown, starting from 1-methylcyclohexene.\u00a0 You must use the starting material at least once, and you may use any viable reagent that delivers no more than two carbons.<\/em><\/strong><\/p>\n

\"Question:<\/p>\n

In this case, the six-carbon ring and the methyl group clearly make up most of the target structure; we simply need to add an ethoxy group across the double bond so it ends up trans<\/em> to the methyl group, on the neighboring carbon.\u00a0 Easier said than done – there is no single step reaction that will do all that.\u00a0 So we will need to design a multistep synthesis.\u00a0 In exam or homework problems there are often constraints put on the synthesis, such as.\u00a0 Here is the initial mapping, including the numbering of the carbons of the starting material skeleton:<\/p>\n

\"Mapping<\/p>\n

Step 2: Identify key bonds to be made<\/h3>\n

Once you know how the starting material maps onto the product, it should be obvious which new bonds need to be made in order to assemble the new skeleton.\u00a0 These new bonds can be divided into two types:<\/p>\n

(a) Key bonds (aka<\/em> bonds which can’t easily be unmade).\u00a0 These include almost all new C-C bonds<\/strong>, as well as any new rings<\/strong> that are made (rare in this class).\u00a0 It also includes new C-N amine bonds<\/strong> or C-O ether bonds<\/strong>.\u00a0 We need to identify these early in our planning.<\/p>\n

(b) Bonds to interchangeable functional groups (aka<\/em> bonds that are easily changed), or C-H bonds that are next to functional groups.\u00a0 We don’t need to worry about these until the end of the planning process.<\/p>\n

For our example synthesis, the key bond we need to make is the C-O ether bond from carbon 2, to add the new ethoxy group.\u00a0 Notice that we also need to make a new C-H bond at carbon 1, cis<\/em> to the new ethoxy group; that’s less obvious because the skeletal structure doesn’t show it explicitly.\u00a0 Although it’s less important than the new C-O bond, we mustn’t forget that we have to make that bond too. So, our synthesis must include an addition step as a key step.<\/p>\n

If we can add the ethoxy group in one step – say by using CH3<\/sub>CH2<\/sub>OH (ethanol) – then we would only have one key bond to make.\u00a0 However, there is no method that adds an -OR group at the anti-Markovnikov<\/em> position; that means we will need to make the other ether C-O bond, from the ethyl group to the oxygen.\u00a0 So our key bonds to make are likely to be the two new C-O bonds<\/strong>.<\/p>\n

Step 3: Consider how to make the key bond(s)<\/h3>\n

This is the key to solving the puzzle of the synthesis; once we’ve worked out how to make the key bond(s), the rest of the synthesis should fall into place (at least, it will with practice).<\/p>\n

The problem here is that we’re trying to do an anti-Markovnikov<\/em> addition to an alkene, and we only know a couple of ways to do that.\u00a0 Do any of them make a new C-O bond?\u00a0 We also want to keep in mind that we need to make a new C-H bond cis to the new C-O bond.\u00a0 (We will also need to make another C-O bond to the ethyl.).<\/p>\n

Please now review section 10.7.5. on the page for section 10.7., Addition involving cyclic intermediates<\/a> (you will need to scroll past halfway down the page).\u00a0 This is the only<\/strong><\/em> reaction you’ve learnt so far that adds across a double bond to place the functional group at the anti-Markovnikov<\/em> position.\u00a0 So that’s your only<\/strong><\/em> choice for the key addition step in the synthesis.\u00a0 What happens if we use this reaction with the starting material we’re given?<\/p>\n

\"Hydroboration-oxidation<\/p>\n

This looks very promising!\u00a0 (Just as well, since it’s our only option for an addition reaction!)\u00a0 We have made one of the necessary C-O bonds at the correct position, and as a bonus we also added the new C-H bond cis<\/em> to the C-O. We’re well on our way with this reaction!<\/p>\n

That means we only have one key bond left to make – the other C-O bond.\u00a0 We need a way to convert an alcohol R-OH into an ether R-O-R’.\u00a0 Recall from section 9.5<\/a> that the most common way to make an ether is via the Williamson ether synthesis.\u00a0 This is an SN<\/sub>2 reaction between the conjugate base of an alcohol (an alkoxide) R-O–<\/sup>, and an alkyl halide R’-X, to give the ether R-O-R’.\u00a0 Since we already have the alcohol ROH, this is perfect for our needs – we just need to convert our alcohol into its conjugate base, then add the alkyl halide and we’re done!\u00a0 In section 9.5, you learnt that NaH can be used to convert an alcohol into its conjugate base, the alkoxide.\u00a0 Let’s see how that would work in our specific example synthesis:<\/p>\n

 <\/p>\n

\"Williamson<\/p>\n

This completes our synthesis!\u00a0 Note that if the starting alcohol is racemic, the other two structures will also be racemic.\u00a0 If you’re unsure about stereochemistry of reactions, review section 4.5<\/a>.<\/p>\n

Step 4. Adjust functional groups<\/h3>\n

These are reactions where we take the functional groups we made in our key steps, and convert them to the functional groups we need in our product.<\/p>\n

In the example we just examined, we didn’t need to do any additional changes to the functional groups to get to the product.\u00a0 In many synthesis problem these additional steps will be needed.\u00a0 Some examples of these functional group conversions are shown in this reaction map:<\/p>\n

\"A<\/p>\n

Step 5: Write out the whole synthesis and check it carefully<\/h3>\n

Once you have written out all the steps, including any functional group changes, you should carefully check your synthesis:<\/p>\n

(a) Count your carbons<\/strong>!\u00a0 It’s easy to make a mistake in a long synthesis, so you perhaps end up with ten carbons instead of the nine you need.\u00a0 Check that you’re making the right product!<\/p>\n

(b) Synthetic traps<\/strong>.\u00a0 Common examples include incompatibilities (e.g., something that would prevent the reaction you want) or competing functional groups (e.g., another group that might also reaction).\u00a0 These types of problems are often not obvious when you’re looking at individual steps, and you only see them when you see the overall synthesis.<\/p>\n

(c) Better way?<\/strong> Now you’ve gone through the whole sequence, look again at the “big picture” to see if there is a better way to do the synthesis.\u00a0 Sometimes a different approach will emerge at this time as you reflect on what you’ve done, and sometimes it may be better than your original.<\/p>\n

Our example synthesis problem was this:<\/p>\n

\"Question:<\/p>\n

And your answer should normally be written out like this<\/p>\n

\"Completed<\/p>\n

In this case, our proposed synthesis is reasonably efficient and it doesn’t have any incompatibilities.\u00a0 It matches with the problem asked at the beginning, and has the correct number of carbons.\u00a0 We have completed the synthesis!<\/p>\n

With synthesis problems, you will find that they become much easier with practice.\u00a0 It is well known that our brains learn to solve complex problems by “chunking” – the way we chunk together letters to make common words and we read the whole word as one concept.\u00a0 The same applies in synthesis, where you will begin to see recognize common patterns, and you may well develop your own favorite reaction sequences. In the next section, I will list a few of my favorite sequences involving the chemistry from chapters 1-10.<\/p>\n

One former student of mine told me that by studying synthesis problems he found that his chess game had improved; he learnt to work back from a desired “checkmate” and trace the possible ways to get there.\u00a0 You will need to memorize many different synthetic reactions and the reagents they use, but as you apply them in synthesis problems they will begin to have meaning.\u00a0 Before you can play chess, you need to learn the moves, but it only becomes meaningful (and fun!) once you start using those moves in a real game. In this way the reagents and conditions become much easier to remember.<\/p>\n

As you get further in this course and learn more reactions, you will begin to see that (just as in chess) there are multiple correct ways to complete a synthesis – maybe hundreds, for a complex target product.\u00a0 However, there are also millions of wrong ways…!<\/p>\n

This video<\/a> from Organic Chemistry Tutor is quite advanced at this point, but may give you a flavor of how a synthesis is put together.<\/p>\n