strategies for organic synthesis

7/27/2019 Strategies for Organic Synthesis

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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 makethings. New pharmaceuticals, food additives, materials, agricultural chemicals, coatings,adhesives and all sorts of other useful new molecules are prepared from simpler more readilyavailable starting materials. There are two aspects to organic synthesis, first the developmentof a synthetic strategy or plan of action and second the actual implementation of that plan in achemical laboratory. The organic chemistry lecture course sequence addresses the first aspectof 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 canstart to acquire by taking an organic laboratory course. Students who master such skills readilyfind jobs in the chemical, pharmaceutical, petroleum, and other industries that employchemists.

The t hree key quest ions:

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 alimited number of reactions used to form carbon-carbon bonds. Knowing how to use themis very important.

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


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2 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 thesecond 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 bromideusing 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 properlyone must determine the regiochemistry and stereochemistry of your reactions. The rulesare often very subtle.

For example if you used a base to form an alkene from 2-bromobutane, whichconfigurational isomer would you get? Would you form 1-butene or a 2-butene (aregiochemistry question)? If you formed 2-butene, would you get the cis-2-butene isomeror 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 andefficient synthesis of a complex molecule. There are thousands of known reactions; regio andstereochemistry are very difficult to control. However, in the introductory courses we havesimplified things by limiting our universe of reactions to a selected number of illustrativeexamples. All the molecules we discuss can be synthesized using the reactions that appear inyour textbook or other course materials. However, with this limited set of reactions we can stillwrite out syntheses of an infinite set of possible molecules. In each synthesis one must considerthe three key questions asked above.

How do you pl an a synt hesis?

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 eachof the three questions above will lead you to the proper reaction sequence more quickly.


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Strategies for Organic Synthesis 3

How about an example?

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

O

Target Molecule

How do I st ar t ?

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 givenmolecule. It is useful to count the carbon atoms so you will know the minimum number ofcarbon-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 3carbon piece and a 8 carbon piece. Since we have to make the 8 carbon piece from startingmaterials of 4 carbons or less it would be nice if we could eventually figure out a way to make aC-C bond in the middle of the fragment by combining two smaller molecules. But that step isnot 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 thatdoes not have to be the case. Perhaps our last step is the hydrogenation of a double or triplebond 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 1shows a selection of possible precursor molecules. Each molecule is connected to thecenter via a retrosynthetic arrow. This arrow means where did I come from? or what sub-target molecule will lead to the molecule of interest?

All sub-target molecules of Scheme 1could be possible precursors of our final TM, but somewould require chemistry of dubious merit. For example the simple alkene precursors on the leftside 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 couldform at C4 just as easily as it could form at C3. This is unacceptable.


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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 synthesesare shown as full reactions in Scheme 2. Notice that a regular reaction arrow is used when allreagents are given.

Scheme 2.

Are the two Williamson syntheses equally good? Perhaps not. The reaction of the alkoxide with3-octane might work but it would also be more likely to give the unwanted elimination sideproduct. The reaction starting with 3-octanol looks better. This gives us a new target. How canyou synthesis 3-octanol?


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So how can we synt hesiz e 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 controllingthe regiochemistry. The bromide substitution would work, but how could we selectively makethe bromide? The reduction of the ketone would be perfect, except normally we would make theketone 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 bestone. 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 lithiumreagents or the alkyl halides used to make them? However, for this exercise we were given thetask of synthesizing the molecule from starting materials containing four carbons or less. Thisgives us a clear best solution to our synthesis. The epoxide route brings together two four carbonstarting materials. It would be the shortest route.

Now we must draw out t he f i na l react i on scheme in the f orwar d d ir ect ion .

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


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Which way is better? It depends. In the laboratory it might be better to isolate the alcohol andto 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 isoften 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 shortestand simplest route, but it is important to always remember that there usually are many routespossible to even a simple molecule.

How about a more d i f f icu l t example?

Sure, no problem. How would you synthesize this hydrocarbon starting with organic compoundscontaining four carbons or less?

There are no funct iona l groups. Where do we st ar t ?

Count your carbons. There are eleven carbon atoms so we are going to have to use at last threecarbon-carbon bond forming reactions.

What reactions you know that would give you a simple alkane as a product? The only way weknow to make an alkane is to hydrogenate away a double or triple bond. Thus our precursor mustbe an alkene or alkyne. Here are some possible alkene precursors.


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Scheme 4.

The target molecule has mirror symmetry so we only have to consider double or triple bonds onone side of the molecule. Scheme 4only shows monoalkenes, compounds with more than onedouble bond or various alkynes would also work. We could also change the stereochemistry ofthe alkenes. In three cases Eisomers have been shown. The Zisomers 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 mostefficient forward synthesis will involve bringing together two smaller molecules of similar size tomake the target molecule. This means that it is usually best to look at the middle of the targetmolecule. Can we divide it into two halves?

Our known carbon-carbon bond forming reactions give us alcohols. An E1 dehydration of alcoholwould give us an alkene. So think about what alcohols would give each of the various alkenes inScheme 3. Some of the eliminations might be quite difficult; they might go the wrong way orgive rearrangements. In most cases the synthesis would be better if we were to convert thealcohol to a halide first followed by an E2 elimination using base.

Scheme 5

How do we nar row down t he many possib i l i t ies?

You might be able to make the target molecule starting with any of the indicated alkenes oralkyl 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


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

How do w e make t he 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 thereaction 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.


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Our re t rosynthesis is now comple te , so le t us wr i t e i t i n the forw ard d i rect i on .

The overall reaction required two moles of 2-butyl Grignard, one mole of formaldehyde and amole of ethylene oxide. It looks pretty simple when it is all written out. Would it be easy to dothis 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 tobe determined. Reactions that look straightforward on paper, dont always work in the lab.

Organic synt hesis is hard wor k, onl y t he 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. The Diels Alder reaction valuable for the assembly of six-membered ringsB. The Chemistry of Aromatic rings substitutions in particularC. Transition Metal Organometallic Chemistry carbon-carbon bond making reactionsD. Enolate Chemistry powerful methods for making carbon-carbon bondsE. Wittig Reaction a versatile method of making alkenesF. Cope and Claisen rearrangements useful rearrangementsG. Amines methods for introducing nitrogen into your compounds.

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


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Synt hesis Pr obl ems. Use the reactions given on the Introductory Organic Reactions Chart

1. For each of the following compounds give two synthetic routes starting with compoundscontaining four carbons or less.

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

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

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

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


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

Where can I f ind t he answer s t o t hese probl ems?

There is no answer key. Most of the problems have more than one solution. God to the coursediscussion board on Blackboard and post your answers and comment on those posted by youclassmates. The TAs and course instructors will monitor your discussions and try to keep you outof trouble


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Selected Introductory Organic Reactionsfrom CHE 321:

H3C CH3

H3C CH3

H2

Lindlar

Na/NH3

H3C H1. NaNH2

2. Br R

H3C

R

H3C H1. NaNH2

2.

H3CO

OH

3. H+


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Practice Problems. Use the reactions given on the Introductory Organic Reactions ChartPost 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 mothLymantria dispar. Propose a synthesis starting from1-bromononane and additional carbon containingcompounds of five carbons or less.

3.An artificial pear fragrance used by Armani inEmporio Armani Elle.Propose a synthesis starting from carbon containingcompounds of four carbons or less.

4. The female sex pheromone of the ruby tiger mothand the painted apple moth (PhragmatogiaFulginosa). Propose a synthesis starting with 1-bromoundecane and additional carbon containingcompounds of five carbons or less. Hint: You cannot use a peracide in the last step it would add toboth double bonds.

5. A component of the odor of Marigolds (Tageteslemmonii). Propose as synthesis starting with carboncompounds of four carbons or less

6. An artificial pear fragrance with the odor of Lily ofthe ValleyPropose a synthesis starting from carbon containingcompounds of four carbons or less.

7. The female sex pheromone of the cigarette beetle(Lasioderma serricorne). Propose a synthesis as amixture of stereoisomers starting with materials offour carbons or less. Controlling the relativestereo-chemistry would be difficult. How could youcontrol the relative chemistry of the centers C6 andC7?


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8. The myxobacterium Stigmatella auranticaca uses arecemic mixture of stigmolone as its fruiting bodyhormone. Propose a synthesis starting with carboncompounds of four carbons or less.

9. The aggregation pheromone of the Colorado potatobeetle (Letinotarsa decemlineata).Propose a synthesis of the racemate starting withcompounds of four carbons or less.

10. Sitophilate is the male produced aggregationpheromone of the granary weevil (Sitophilusgarnarius). It is active as a mixture of enantiomers.Propose a synthesis of the racemate starting withcarbon containing compounds of four carbons orless. Make sure you control the relative

stereochemistry of the methyl and hydroxyl groups.

11. This compound is a sex hormone of the Cadis Fly.Propose a synthesis of the racemate starting withcompounds of four carbons or less.

12. Rove beetles use a complex mixture of compoundsfor 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 withcompounds of four carbons or less.

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


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15. An artificial fragrance with the odor of grapefruitPropose a synthesis of the racemate starting withcompounds of four carbons or less.

16. Linalool is isolated from the herb Basil (Ociumbasilicum) and many other plants. Propose asynthesis of the racemate starting with compoundsof four carbons or less.

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

18.O

6-methyloctanal

A component of the odor of the Japanese Yuzufruit. Propose a synthesis of the racemate startingwith compounds of four carbons or less. Propose asynthesis of the racemate starting with compoundsof 4 carbons or less.

19.Sex pheromone of the pink bollworm moth.Proposea synthesis starting with compounds of four carbonsor less.

20. A component of the balm of the Populus Basamiferatree.Propose a synthesis of the racemate startingwith bromobenzene and other compounds of fourcarbons or less.

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