Study Guide 1.

Strategies for Organic Synthesis (with CHE 321 Chemistry)

Joseph W. Lauher, Stony Brook University (CHE 326 Spring 2013)

One of the things that makes chemistry unique among the sciences is synthesis. Chemists make things. New pharmaceuticals, food additives, materials, agricultural chemicals, coatings, adhesives and all sorts of other useful new molecules are prepared from simpler more readily available starting materials. There are two aspects to organic synthesis, first the development of a synthetic strategy or plan of action and second the actual implementation of that plan in a chemical laboratory. The organic chemistry lecture course sequence addresses the first aspect of the problem; the development of strategies for synthesis is the subject of this study guide. The second aspect, the actual synthesis, requires real skill and training, something that you can start to acquire by taking an organic laboratory course. Students who master such skills readily find jobs in the chemical, pharmaceutical, petroleum, and other industries that employ chemists. The three key questions: When planning an organic synthesis there are usually three key questions that one must ask. 1. How can I build the desired carbon skeleton? The assembly of the carbon skeleton is the key part of any synthesis. There are only a limited number of reactions used to form carbon-carbon bonds. Knowing how to use them is very important.

These six compounds all have the same carbon skeleton, the same arrangement of C-C bonds. If you could make any one of these molecules you could convert it to any of the others simply by interconverting the functional groups.

CHE 326 Study Guides 2. How do I introduce the necessary functional groups? Functional groups make the molecule. Knowing how to add a functional group is the second key part of synthesis. Most often one functional group is prepared from another.

For example a alcohol can be oxidized to a ketone using PCC or converted to a bromide using HBr. Interconverting functional groups is a common synthetic route. 3. How do I control the regio - and stereochemistry of my reactions? Controlling the structure of your product molecule is very important. To do this properly one must determine the regiochemistry and stereochemistry of your reactions. The rules are often very subtle.

For example if you used a base to form an alkene from 2-bromobutane, which configurational isomer would you get? Would you form 1-butene or a 2-butene (a regiochemistry question)? If you formed 2-butene, would you get the cis-2-butene isomer or the trans-2-butene isomer (a stereochemistry question)? In the real world one needs to know a vast amount of organic chemistry to plan a successful and efficient synthesis of a complex molecule. There are thousands of known reactions; regio and stereochemistry are very difficult to control. However, in the introductory courses we have simplified things by limiting our universe of reactions to a selected number of illustrative examples. All the molecules we discuss can be synthesized using the reactions that appear in your textbook or other course materials. However, with this limited set of reactions we can still write out syntheses of an infinite set of possible molecules. In each synthesis one must consider the three key questions asked above. How do you plan a synthesis? The simple answer is to work backwards, one step at a time, implementing known reactions. Often there will be more than one possible reaction sequence. A little thought devoted to each of the three questions above will lead you to the proper reaction sequence more quickly.

Strategies for Organic Synthesis How about an example?

Ok. How would you synthesize the following ether starting with organic compounds containing four carbons or less?

Target Molecule

How do I start?

Count the carbon atoms and identify your functional groups. You need to know the functional groups so you know which reactions in your reaction library can be used to yield the given molecule. It is useful to count the carbon atoms so you will know the minimum number of carbon-carbon bond forming reactions you will eventually need in your synthesis.

In this case recognize that the compound is an ether and that it is made from two fragments, a 3 carbon piece and a 8 carbon piece. Since we have to make the 8 carbon piece from starting materials of 4 carbons or less it would be nice if we could eventually figure out a way to make a C-C bond in the middle of the fragment by combining two smaller molecules. But that step is not yet obvious so let start by considering what the last step of the synthesis would be. One logical approach is to use the last step in the reaction to make the ether linkage. But that does not have to be the case. Perhaps our last step is the hydrogenation of a double or triple bond left over from some previous step in the synthesis. There are lots of possibilities including many that would use reactions we have not yet studied in the course. Scheme 1 shows a selection of possible precursor molecules. Each molecule is connected to the center via a retrosynthetic arrow. This arrow means where did I come from? or what subtarget molecule will lead to the molecule of interest? All sub-target molecules of Scheme 1 could be possible precursors of our final TM, but some would require chemistry of dubious merit. For example the simple alkene precursors on the left side of Scheme 1 could be converted to the TM by the oxymercuration addition of propanol. Whats the problem? There is nothing to control the regiochemistry. The ether linkage could form at C4 just as easily as it could form at C3. This is unacceptable.

CHE 326 Study Guides

Scheme 1.

The alcohol and bromide precursors are obvious candidates for a Williamson ether synthesis. Each would be paired with a matching propane derivative. These two possible ether syntheses are shown as full reactions in Scheme 2. Notice that a regular reaction arrow is used when all reagents are given.

Scheme 2. Are the two Williamson syntheses equally good? Perhaps not. The reaction of the alkoxide with 3-octane might work but it would also be more likely to give the unwanted elimination side product. The reaction starting with 3-octanol looks better. This gives us a new target. How can you synthesis 3-octanol?

Strategies for Organic Synthesis

So how can we synthesize an alcohol? Here are some possible routes to 3-octanol.

Scheme 3. We have lots of ways of making alcohols, but for our synthesis some will be better than others. The addition of water to a double bond will give an alcohol, but we have no way of controlling the regiochemistry. The bromide substitution would work, but how could we selectively make the bromide? The reduction of the ketone would be perfect, except normally we would make the ketone from the alcohol, so we would have a circular synthesis. The three reactions with lithium reagents would all work. It is just a matter of choosing the best one. In the laboratory we would make our choice on the basis of starting material availability. Do we have a source of the proper aldehyde or the epoxide? Do we have the required lithium reagents or the alkyl halides used to make them? However, for this exercise we were given the task of synthesizing the molecule from starting materials containing four carbons or less. This gives us a clear best solution to our synthesis. The epoxide route brings together two four carbon starting materials. It would be the shortest route. Now we must draw out the final reaction scheme in the forward direction.

This completes the synthesis. It has only two steps, each of two parts. In principle we could even have a shorter synthesis, skipping the alcohol completely.

CHE 326 Study Guides

Which way is better? It depends. In the laboratory it might be better to isolate the alcohol and to purify it before going on to the ether. Or maybe it would be best to go directly to the ether. It depends upon such things as isolation and purification procedures. This sort of decision is often made in the laboratory. It is not an essential part of the overall strategy. The epoxide route suggests one other possible precursor listed back in Scheme 1. We could have opened the epoxide with an acetylide.

Which route is the best? Opening the epoxide with butyl lithium would seem to be the shortest and simplest route, but it is important to always remember that there usually are many routes possible to even a simple molecule. How about a more difficult example? Sure, no problem. How would you synthesize this hydrocarbon starting with organic compounds containing four carbons or less?

There are no functional groups. Where do we start? Count your carbons. There are eleven carbon atoms so we are going to have to use at last three carbon-carbon bond forming reactions. What reactions you know that would give you a simple alkane as a product? The only way we know to make an alkane is to hydrogenate away a double or triple bond. Thus our precursor must be an alkene or alkyne. Here are some possible alkene precursors.

Strategies for Organic Synthesis

Scheme 4. The target molecule has mirror symmetry so we only have to consider double or triple bonds on one side of the molecule. Scheme 4 only shows monoalkenes, compounds with more than one double bond or various alkynes would also work. We could also change the stereochemistry of the alkenes. In three cases E isomers have been shown. The Z isomers would work just as well. But how do we choose one compound out of our many different candidates? We need to think of our overall goal. We need to build our molecule out of smaller fragments. Often the most efficient forward synthesis will involve bringing together two smaller molecules of similar size to make the target molecule. This means that it is usually best to look at the middle of the target molecule. Can we divide it into two halves? Our known carbon-carbon bond forming reactions give us alcohols. An E1 dehydration of alcohol would give us an alkene. So think about what alcohols would give each of the various alkenes in Scheme 3. Some of the eliminations might be quite difficult; they might go the wrong way or give rearrangements. In most cases the synthesis would be better if we were to convert the alcohol to a halide first followed by an E2 elimination using base.

Scheme 5 How do we narrow down the many possibilities? You might be able to make the target molecule starting with any of the indicated alkenes or alkyl bromides, but they would not be equally easy. Choose one where the elimination is clean. It is also good to place the double bond near the middle of the molecule. Since our target

CHE 326 Study Guides

molecule has symmetry it is also nice to take advantage of the symmetry and to choose the one symmetrical alcohol. This gives us the following scheme and new target molecule.

How do we make the alcohol? We can use a Grignard or alkyl Lithium compound derived from an alkyl halide and an aldehyde. The molecule has symmetry so there is only one choice of reactants.

Now we have two simple molecules to worry about. The bromide can come from an alcohol which is the product of another Grignard reaction.

The aldehyde must come from the oxidation of an alcohol. This alcohol could come from the reaction of a five carbon Grignard reagent with formaldehyde, but it would be shorter to use a four carbon Grignard reagent and ethyleneoxide, the simplest epoxide.

Strategies for Organic Synthesis Our retrosynthesis is now complete, so let us write it in the forward direction.

The overall reaction required two moles of 2-butyl Grignard, one mole of formaldehyde and a mole of ethylene oxide. It looks pretty simple when it is all written out. Would it be easy to do this in the lab? The short answer is simple. No! It wouldnt. Procedures for the separation, isolation, purification and characterization of each of product along the synthetic route need to be determined. Reactions that look straightforward on paper, dont always work in the lab. Organic synthesis is hard work, only the best can succeed! What is coming in CHE 326? In the second semester your arsenal of synthetic tools will be augmented by many versatile organic reactions. These include: A. B. C. D. E. F. G. The Diels Alder reaction valuable for the assembly of six-membered rings The Chemistry of Aromatic rings substitutions in particular Transition Metal Organometallic Chemistry carbon-carbon bond making reactions Enolate Chemistry powerful methods for making carbon-carbon bonds Wittig Reaction a versatile method of making alkenes Cope and Claisen rearrangements useful rearrangements Amines methods for introducing nitrogen into your compounds.

We will also explore various biosynthetic pathways, Natures own synthetic methodology.

10

CHE 326 Study Guides

Synthesis Problems. Use the reactions given on the Introductory Organic Reactions Chart 1. For each of the following compounds give two synthetic routes starting with compounds containing four carbons or less.

Show how you could synthesize the following alkenes starting with compoundss containing four carbons or less. More than one step is required.

3. Show how you could synthesize the following alcohols starting with compounds containing four carbons or less. More than one step is required. There is more than one synthetic route for each case. Can you find the shortest one?

4. Give syntheses for the following compoundss starting with molecules containing four carbons or less.

5. Give syntheses for each of the following compoundss starting with molecules containing four carbons or less. Multiple steps will be required.

Strategies for Organic Synthesis

11

6. Give a synthesis of the following cyclic ethers using starting materials containing four carbons or less.

7. How can you control the regiochemistry of your reaction to synthesis the following compounds (as racemates) using starting materials of four carbons or less?

8. Give a synthesis of the following compounds using cyclohexanol and other starting materials containing four carbons or less.

Where can I find the answers to these problems? There is no answer key. Most of the problems have more than one solution. God to the course discussion board on Blackboard and post your answers and comment on those posted by you classmates. The TAs and course instructors will monitor your discussions and try to keep you out of trouble

12

CHE 326 Study Guides

Selected Introductory Organic Reactions from CHE 321

H 3C CH3 H2 Lindlar Na/NH3 1. NaNH2 2. Br H 3C H 1. NaNH2 2. O 3. H+ R

H 3C H3 C

CH3 H

H3 C R OH H 3C

Strategies for Organic Synthesis

13

Practice Problems. Use the reactions given on the Introductory Organic Reactions Chart Post your answers on the Blackboard Discussion Board.

1.

Key ingredient of the Chinese Wisteria plant. Propose a synthesis from bromobenzene and other carbon compounds of three carbons or less. Hint: protect one alcohol before you make the second.

2.

The female sex pheromone of the gypsy moth Lymantria dispar. Propose a synthesis starting from 1-bromononane and additional carbon containing compounds of five carbons or less.

3.

An artificial pear fragrance used by Armani in Emporio Armani Elle. Propose a synthesis starting from carbon containing compounds of four carbons or less.

4.

The female sex pheromone of the ruby tiger moth and the painted apple moth (Phragmatogia Fulginosa). Propose a synthesis starting with 1bromoundecane and additional carbon containing compounds of five carbons or less. Hint: You can not use a peracide in the last step it would add to both double bonds.

5.

A component of the odor of Marigolds (Tagetes lemmonii). Propose as synthesis starting with carbon compounds of four carbons or less

6.

An artificial pear fragrance with the odor of Lily of the Valley Propose a synthesis starting from carbon containing compounds of four carbons or less.

7.

The female sex pheromone of the cigarette beetle (Lasioderma serricorne). Propose a synthesis as a mixture of stereoisomers starting with materials of four carbons or less. Controlling the relative stereo-chemistry would be difficult. How could you control the relative chemistry of the centers C6 and C7?

14

CHE 326 Study Guides

8.

The myxobacterium Stigmatella auranticaca uses a recemic mixture of stigmolone as its fruiting body hormone. Propose a synthesis starting with carbon compounds of four carbons or less.

9.

The aggregation pheromone of the Colorado potato beetle (Letinotarsa decemlineata). Propose a synthesis of the racemate starting with compounds of four carbons or less. Sitophilate is the male produced aggregation pheromone of the granary weevil (Sitophilus garnarius). It is active as a mixture of enantiomers. Propose a synthesis of the racemate starting with carbon containing compounds of four carbons or less. Make sure you control the relative stereochemistry of the methyl and hydroxyl groups. This compound is a sex hormone of the Cadis Fly. Propose a synthesis of the racemate starting with compounds of four carbons or less.

10.

11.

12.

Rove beetles use a complex mixture of compounds for chemical defense. This is one component. Propose a synthesis of the racemate starting with compounds of four carbons or less.

13.

A major odor component of the Meadow Mushroom. Propose a synthesis of the racemate starting with compounds of four carbons or less.

14.

A component of the oil of Roman chamomile (Chamaemelum nobile). Propose a synthesis starting with compounds of four carbons or less.

Strategies for Organic Synthesis

15

15.

An artificial fragrance with the odor of grapefruit Propose a synthesis of the racemate starting with compounds of four carbons or less.

16.

Linalool is isolated from the herb Basil (Ocium basilicum) and many other plants. Propose a synthesis of the racemate starting with compounds of four carbons or less.

17.

Isolated from Atemesia herba-alba. Propose a synthesis starting with compounds of four carbons or less.

18.
6-methyloctanal

A component of the odor of the Japanese Yuzu fruit. Propose a synthesis of the racemate starting with compounds of four carbons or less. Propose a synthesis of the racemate starting with compounds of 4 carbons or less.

19.

Sex pheromone of the pink bollworm moth.Propose a synthesis starting with compounds of four carbons or less.

20.

A component of the balm of the Populus Basamifera tree.Propose a synthesis of the racemate starting with bromobenzene and other compounds of four carbons or less.