Introduction to Organic Synthesis

CM3001 Dr. Alan Ford (Lab 415)

text: Willis & Wills Organic Synthesis (OUP)

To state the obvious:

Synthesis is the process of making a desired compound using chemical reactions. More often than not, more than one step is involved.

The importance of synthesis

1. Total synthesis of interesting and/or useful natural products2. Industrially important compounds3. compounds of theoretical interest4. structure proof5. development of new synthetic methodology6. importance to other areas of science and technology

Examples

Natural products eg. steroids, prostaglandins, alkaloids

15-Methyl PGF2α (prostaglandin) Epibatidine (South American frog alkaloid)< 15 mg isolated from 750 frogs

Industrially important compounds such as pharmaceuticals, agrochemicals, flavours, dyes, cosmetics, monomers and polymers

Naproxen (painkiller) Carbaryl (insecticide) Sarin (nerve gas)

Isobutavan Methylenedioxymethamphetamine, MDMA(smells of mint chocolate) (Ecstasy)

"5 CB" (liquid crystal) Kevlar (fancy polymer)

Theoretically interesting molecules

Cubane meta para Cyclophane

Structure proof While spectroscopy and crystallography are used to determine molecular structures, unambiguous total synthesis is still important

S-(+)-Chelonin B (marine sponge alkaloid)

New methodology New ways to make molecules, improvement of existing ways, ways of doing what was previously impossible

Science and Technology Materials with special applications; molecular switches, non-linear optics, nanotechnology

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Basic Steps of Solving Synthetic Problems

1) Choice of TARGET MOLECULE (TM)

2) Consideration of applicable synthetic methodology

3) Design of synthetic pathway

4) Execution of the synthesis

—these steps are highly interactive

Approaching the design of a synthesis (Part One)

For simple molecules it can be obvious just by looking at the target structure, for example:

Cyclohexyl bromide

Bromoalkanes are available from alkenes or from alcohols

Methyl benzoate

Esters are available from carboxylic acids by reaction with alcohols; benzoic acid is available from toluene

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cis-3-octene

cis-Alkenes can be selectively prepared by partial reduction of alkynes; alkynes are accessible via acetylide chemistry.

Approaching the design of a synthesis (Part Two)

For more complex molecules, it helps to have a formalised, logic-centred approach;RETROSYNTHETIC ANALYSIS

Retrosynthetic analysis is the process of working backwards from the target molecule to progressively simpler molecules by means of DISCONNECTIONS and/or FUNCTIONAL GROUP INTERCONVERSIONS that correspond to known reactions. When you've got to a simple enough starting material (like something you can buy [and usually is cheap]) then the synthetic plan is simply the reverse of the analysis. The design of a synthesis needs to take into account some important factors.

1) it has to actually work2) in general, it should be as short as possible3) each step should be efficient4) side products (if formed) and impurities (there always are) should be easily separable from the

desired product5) environmental issues may be relevant6) there's more than one way to skin a cat

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Example retrosynthetic analysis

Target molecule:

therefore the target molecule could be synthesised as follows:

What is a synthon?

When we disconnect a bond in the target molecule, we are imagining a pair of charged fragments that we could stick together, like Lego® bricks, to make the molecule we want. These imaginary charged species are called SYNTHONS. When you can think of a chemical with polarity that matches the synthon, you can consider that a SYNTHETIC EQUIVALENT of the synthon. Thus,

≡ an aldehyde is a synthetic equivalent for the above synthon.There can be more than one synthetic equivalent for a given synthon, but if you can't think of one...try a different disconnection.

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Always consider alternative strategies.

a second possible synthesis:

Similarly

thus a third possible synthesis is

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Besides disconnections, we can also consider functional group interconversion. Our target molecule is a secondary alcohol, which could be prepared by reduction of a ketone. This is represented as follows:

synthesis number four

Analysis number five:

Synthesis number five:

Disconnecting heteroatoms can also be a good idea:

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6th approach:

There are other possibilities, but let's not bother with any more.

How do you choose which method?

Personal choice. If you have a favourite reagent, or if you are familiar with a particular reaction (or if you have a strong aversion to a reaction/reagent) then this will affect your choice. Also you need to bear in mind the efficiency of the reactions involved, and any potential side reactions (for example, self-condensation of PhCOMe in method 4).

DEFINITIONS

TARGET MOLECULE (TM) what you need to make

RETROSYNTHETIC ANALYSIS the process of deconstructing the TM by breaking it into simpler molecules until you get to a recognisable SM

STARTING MATERIAL (SM) an available chemical that you can arrive at by retrosynthetic analysis and thus probably convert into the target molecule

DISCONNECTION taking apart a bond in the TM to see if it gives a pair of reagents

FUNCTIONAL GROUP INTERCONVERSION (FGI)

changing a group in the TM into a different one to see if it gives an accessible intermediate

SYNTHON conceptual fragments that arise from disconnection

SYNTHETIC EQUIVALENT chemical that reacts as if it was a synthon

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Some synthons and synthetic equivalents

synthon equivalent(s)

RCl, RBr, RI, ROMs, ROTsonly when R = ALKYL

,

, ,

(alkyl; NOT "RH + base")RMgBr, RLi, R2CuLi, other organometallic reagents

,

nb// make sure you don't lose CH2 groups if you represent eg. RCH2 as R— (viz. make sure the product has the right number of carbon atoms!)

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Latent Polarity

Think about some of the reactions we've looked at for carbonyl compounds:

these polarities apply quite generally:

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The partial positive and negative charges indicate the latent polarity of the bonds in a molecule. They help us choose the synthons for key disconnections in a retrosynthetic analysis. viz.

one of the disconnections we saw earlier.

Latent polarity in bifunctional compounds

Consider a 1,3-disubstituted molecule, e.g.

When the latent polarities in a bifunctional molecule overlap they reinforce each other, this is termed CONSONANT POLARITY. In these circumstances the analysis is straightforward.thus,

Similar principles apply for other 1,3-systems:

etc.

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The same applies to 1,5-disubstitution

But what about 1,4-disubstitution?

The polarities don't overlap and are termed DISSONANT. Any disconnection we try will result in a synthon that has the "wrong" polarity.

One way to get around this is by judicious placement of heteroatoms:

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The German word UMPOLUNG, meaning polarity reversal is used to describe the situation where the polarity in a compound is deliberately changed to facilitate a particular reaction.

example:

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Equivalents for synthons with reversed polarity

synthon equivalent(s)

, or

, or

,or MeNO2 + base ("Nef reaction")

NaCN

footnote to table

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Latent polarity and FGI (a quick consideration)

SURVEY OF FUNCTIONAL GROUP INTERCONVERSIONS

note: This is not supposed to be an exhaustive list of organic chemistry, nor is it supposed to tell you anything you don't already know [for more information see relevant lecture notes or consult a textbook]. The idea is to demonstrate how functional groups are related.

--note 2: the schemes are not repeated here; consult the paper copy that was given out during the lecture. You were there, right?

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Strategy in retrosynthesis

1) Consider different possibilities. Try a number of disconnections and FGI's. Try to keep the number of steps down, and stick to known & reliable reactions. In real life, a synthesis has to be economically viable.

2) Whenever possible, go for a convergent route rather than a linear one, as this will lead to a higher overall yield

eg.

Linear vs. convergent synthesis:assume 80% yields (optimistic!)

Linear:

Convergent:

The purely convergent synthesis is an ideal; virtually all real synthesis are linear to some degree

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3) Aim for the greatest simplification

make disconnections towards the middle of the molecule (this is more convergent anyway)

disconnect at branch points use symmetry where possible

eg. (towards the middle)

eg. (at branches)

eg. (look for symmetry)

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4) Add reactive functional groups at a late stage in the synthesis so they aren't carried through steps where they could react to give side products.

Alternatively, potentially reactive groups can be protected or masked so they don't react, eg. reduction of an ester in the presence of a ketone

Note that protection strategy requires two extra steps (must be efficient); better syntheses minimise the use of protecting groups.

A masked group is a functional group that is introduced and can be converted into a different one at a later stage ( remember EVL)

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5) Sometimes it helps the retrosynthesis if you add a functional group to facilitate bond formation (Functional Group Addition). An example of this is acetoacetic ester synthesis:

Thus:

(acetoacetic ester is much more easily deprotonated than acetone)

The synthesis therefore is

The strategy of FGA applies especially in the case of molecules containing no reactive functional groups:

alternatively:

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Ring Closing ReactionsSynthesis of carbocyclic moleculesSame approach as to acyclic systems. The probability of reaction between two functional groups is higher if:a) reaction is intramolecular (faster reaction)b) the distance between the two groups is shorter

e.g. Intramolecular alkylation:

Intramolecular acylation eg. the Dieckmann cyclisation; especially good for 5-membered rings:

condensation:

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Bicyclic molecules are prepared from cyclic precursors following similar principles.

A special example of condensation is the Robinson annulation (opinions vary as to the spelling). It has been widely used in classical steroid synthesis. It involves Michael addition followed by intramolecular cyclisation:

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Medium and Large Rings (8-11 membered and 12+)

Intramolecular reaction is less favoured with bigger rings. Often, high-dilution conditions and slow addition can be used to suppress intermolecular reaction and hence promote ring closure.

eg.

similarly

Another reaction which works well for such systems is the acyloin reaction. This is the intramolecular dimerisation of a diester via a one-electron reduction. The reaction is heterogeneous, taking place at the surface of molten sodium metal, so high dilution is not required.

eg

and

Cycloaddition reaction (Diels-Alder)

Generic reaction (in retrosyntheic terms):

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eg

&

These reactions are concerted reactions, usually they are highly stereospecific. This is because the reactions are governed by Frontier Orbital Theory. The actual rules of frontier orbital theory don't interest us at the moment, all we need is a simple guideline we can remember:

Unsymmetrical Diels-Alder reactions:

note that the 1,3-disubstituted product is the minor product in both cases

specific example:

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Disconnections & Functional Group Interconversion in Aromatic Systems

Some reactions used in aliphatic systems don't apply for aromatic systems (SN1 and SN2 reactions, for example, are extremely unfavourable for ArX. There is a whole bunch of other reactions that apply for aromatic systems.

eg.

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Some other reactions

The last reaction above is a particularly useful application of organocopper reagents. Although the mechanism is quite complicated, it's the result we're interested in at the moment. It's a transformation that is not always easy to achieve by more conventional means.

In planning synthesis of polysubstituted aromatics, the order of reactions is important to ensure that the reagents are compatible and to take advantage of the directing effect of existing substituents:

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Examples

Birch Reduction

Partial reduction of aromatic systems by (usually) sodium in liquid ammonia. It's an example of dissolving metal reduction. Such methods used to be quite popular but most applications have been replace by modern hydride reagents. Dissolving metal reduction does still have it's uses though, and the Birch reduction is one of them. (also recall the specific reduction of alkynes to trans-alkenes)The typical conditions involve liquid ammonia (bp. −33 °C) and sodium metal, in the presence of a proton source (usually an alcohol, EtOH).

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Examples

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Fusing Rings onto aromatic systems

The classical Hayworth naphthalene synthesis. The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride.

Thus:

other substitution patterns can be similarly obtained.

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Blocking positions in aromatic rings

Functional groups that are introduced reversibly, or can be easily cleaved under mild condtions, can be used to access otherwise hard-to-make compounds

Transformations of Aromatic Systems--(Summary Scheme)

Consult the handout.

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Overall Summary

To devise a synthesis:

1) Examine the TM; recognise functional groups and key structural features. In an exam you may be given a SM, if this is the case, check how it relates to the TM

2) Use FG's present to help indicate disconnection points. Use latent polarities, umpolung and FGA to help if neccessary

3) Consider FGI's appropriate to the TM; consider disconnections at branch points and heteroatoms. Be convergent—disconnect between FG's separated by a couple of carbon atoms

4) Keep the number of steps as low as reasonably possible, but do use protecting groups where neccessary

5) Disconnect to good SM's:

straight chain monofunctional compounds branched monofunctional compounds containing six carbon atoms or fewer (for these

purposes, including allyl, alkenyl and cycloalkyl compounds) simple mono- and disubstituted benzenes common bifunctional compounds (acetoacetate esters, malonate derivatives etc.) hint: concerning regents & SM's...have you seen them before (like in tutorials?)

Further reading

I take full responsibility for any mistakes and tyops, after all, I'm just a man. I encourage all students consult with higher authorities, and you could do a lot worse than look at some of these:

o Organic Synthesis: The Disconnection Approach, S. Warreno Classics in Total Synthesis I & II, K.C. Nicolaou et al.o Advanced Organic Chemistry, J. Marcho Comprehensive Organic Transformations, R.C. Larocko Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts

Go to the Library, it's free to get in.

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