ORGANIC SYNTHESIS

The Organic Synthesis section has been created and is maintained by Professor Wilbert Rivera Muñoz .

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ORGANIC SYNTHESIS
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 ORGANIC SYNTHESIS METHODOLOGIES

The total synthesis of an organic compound would require starting each time from the elements that compose it. However, it is well known that simple organic compounds such as urea, methane, methanol, acetylene, acetic acid, ethanol can be obtained from the elements, and so on, increasingly complex structures can be built.

However, this is neither practical nor necessary as there are a large number of organic compounds that are commercially available or economically available and these can be used as starting materials. Strictly speaking, all of them derive from the elements that make them up or can be derived from them, so any synthesis that is undertaken from these raw materials will be “formally” a total synthesis.

The synthesis methodologies to face a successful synthesis have been changing with the passage of time and the development of chemistry itself as a science, hence the following are known:

  •    Methodology of the “direct association”
  •     Methodology of the “intermediate approach”
  •     Methodology of "logical analysis"


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ORGANIC SYNTHESIS
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The elaboration of a " synthesis tree " based on generating intermediate or precursor molecules, step by step in the antithetic direction (retrosynthesis), that is, starting from the objective molecule, constitutes a method that can be better understood by considering the following general principles of said process.

1.       Start with the final structure (MOb). Starting from the final structure, the target molecule, work backwards (retrosynthesis) until easily accessible raw materials are obtained. If the starting raw material is specified in the synthesis problem, this only limits the number of possible synthetic routes to be addressed.

2.       Characterization of the target molecule (MOb ). When examining the structure of the target molecule, it is necessary to answer the following questions:

to.       What kind of compound is it?

b.       What functional group(s) does it contain?

c.       What is the nature of the carbon skeleton?

d.       Does the molecule have a normal or branched alkyl chain?

and.       Does it contain rings and are they cycloalkyl or aromatic?

F.         Does the MOb have actual or potential symmetry?

3.       The Functional Group .  In this regard, it will also be good to answer the following questions:

to.       Is the reactivity, sensitivity and instability of the functional groups that the MOb possesses known?

b.       What general methods are available for its preparation?

c.       Which of them is applicable to the specific functional group of the problem molecule?

4.       Stereochemical aspects . It will be analyzed in the MOb, preferably:

to.       chirality centers

b.       Shaping and configuration of rings

c.       Proximity effects between groups

5.       The carbonate skeleton .  The main problem in most organic syntheses is the construction of the carbon skeleton. The exchange of functional groups (IGFs) is often simple to do, such as ketone to alcohol, aldehyde to acid, or alcohol to bromide. The questions that are asked regarding the construction of CC links are related to those that have already been raised regarding the functional group.

to.       Are some of the methods available to form functional groups applicable to generate CC links? If so.

b.       Is the method compatible with the specific carbon skeleton of the target molecule? If it is not.

c.       Is there a procedure for forming a carbon chain that produces a convertible function to the required one?

6.       Precursor Molecules (PM)

The analysis of the structure of the problem molecule and the consideration of the questions posed in steps 1) to 5), will give rise to two possible types of precursor molecules. One of them contains a functional group equivalent to that of the final structure.

The other is a compound with fewer carbon atoms than the target molecule. When the latter are brought together, the final carbon chain and the required functionality are achieved.

The generation of any of these types of precursor molecule should result in a simplification of the problem.

In general, if a projected path leads to precursors that are more difficult to synthesize than the problem itself (target), another path must be sought.

tree_of_synthesis.gif


 

Fig. 1. TREE OF SYNTHESIS

The generation of precursor molecules, until  reaching the starting materials, generates a series of structures, which together form a kind of tree, fig.1.  This is where the name of the synthetic method comes from.


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Synthesis of n-Hexanol (MOb 02)

Solution: The n-Hexanol (MOb 02) is a primary alcohol, whose carbon chain does not present ramifications. Therefore, the strategy is reduced to looking for reactions that allow the chain to grow in a good number of carbon atoms. It is not advisable that the growth of the chain is one by one, since this path would lead to a synthesis plan with many stages, consequently a low yield.

As such, the opening of epoxide rings by a Grignard compound can be adequate for this purpose; as it can also be combined with acetylenic synthesis (use of derivatives of sodium acetylide and subsequent saturation of the triple bond).

The epoxide needed to combine with the Grignard is prepared from an alkene and a peracid acid.  Thus, the present synthesis plan is deduced, where the starting materials can be acetylene and ethanol.

synthesis_of_the_mob02.gif

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Formation of enols and enolates

The alpha of compounds containing the carbonyl group (aldehydes, ketones, esters, diketones, diesters, nitrates, nitriles, etc.), is the center of many CC bond formation reactions. Due to the acidity of the H to, they suffer a to-deprotonation in the presence of a suitable base, with the consequent formation of a carbanion. The resulting negative charge on C to to C=O, it is stabilized by resonance, by the same carbonyl group.

stability_of_enolates.png

The selection of the base, for the formation of enolates, is subject to the fact that the pKa of the conjugate acid of the base must be greater by at least three units than the pKa of the carbonyl compound that has Hto acidic

acetone.png

pKto = 20

MeO-  pKto = 15

Unfavorable enolate formation

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pKto = 10

youBuO-  pKto = 19

Very favorable enolate formation

Formation of enolates:

enolesc-enolest.png

¨       The kinetic enolate

It occurs because the substrate has Hα, easily accessible for deprotonation by means of a typical base such as LDA (pKa  approx  30)

LDA (lithium diisopropylamide) is a strong, non-nucleophilic, sterically hindered base.

lda.png

¨       Enolates of esters:

Esters are susceptible to a substitution reaction for the base,  LDA can be problematic, which is why the non-nucleophilic base (lithium isopropylcyclohexyl amide) is used with esters.

enolato_de_stera.png

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¨       Thermodynamic enolate:

A reversible deprotonation can lead to more stable enolates, which occurs when the more substituted C=C of the enol form is obtained.

emolate_thermodynamic.png

Typical conditions to form thermodynamic enolates are: RO-M+ in ROH as protic solvent (pKa of ROH =  15 to 18).

Kinetic and thermodynamic enolates can be trapped, isolated, separated, and purified to obtain regiochemically pure enolates. This can be accomplished by the formation of enol and silylene ether acetates.

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Reactions of Enols and Enolates

Aldol reactions and the so-called condensation reactions of carbonyl compounds and others  of this type, which can form enol and enolate structures, participate in a large group of important reactions that allow us to understand the existence of an immense number of molecules resulting from the interaction of enols or enolates with a series of electrophilic groups.

The study of this type of reaction has made it possible to verify and establish the existence of two reaction mechanisms through which they occur, as explained below:

TO)      When is it used acid As a catalyst, the carbonyl compound is initially protonated and then tautomerized to its form enolic, which is a nucleophile on the alpha carbon to the carbonyl group. The same acid medium is enough to activate the carbonyl group of another molecule, making it highly electrophilic, which generates optimal conditions to produce an unsaturated carbonyl compound.

enol_y_enolato.png

The reaction normally proceeds until the dehydration of the enol formed, catalyzed by the same acid of the reaction.

dehydration_of_enol.png

B)  When the catalyst is a base, such as an alkoxide, the aldol-type reaction proceeds via the nucleophilic attack of the resonance-stabilized enolate on the carbonyl group of another molecule.

enolato_aldol.gif

By dehydration of the aldol, catalyzed by base, the dehydrated final product is formed.

As in the previous case, the dehydration catalyzed by bases (sometimes written as a single step), allows you to control the reaction and produce a dehydrated final product. In some cases, the formation of enolates is irreversible.

how it looks  only a catalytic amount of base is required in some cases, the most usual procedure is to use an amount stoichiometric strong base such as LDA either NaHMDS. In this case, enolate formation is irreversible, and the aldol product is not formed until the metal alkoxide of the aldol product is protonated in a later step.