20.8: Synthesis using nucleophilic addition chemistry

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Carbon-carbon bond forming reactions

Many of the reactions seen in this chapter involve carbon-carbon bond forming reactions, which often represent the key steps in multistep syntheses. This is because this chapter showed the use of strongly nucleophilic carbon (Organometallics, Wittig reagents or enolates) reacting with the electrophilic carbon of the C=O.

The chart below shows how to design a synthesis for the most suitable carbon-carbon bond formation. It uses a five-carbon target as a standard model; you should adapt it to your specific carbon skeleton. The product is shown on the left, and the squiggly arrow shows the “disconnection,” equivalent to the bond that will be made in the synthesis (shown as a dashed line). The => arrow means “is made from.”

Organometallics and Wittig reactions in synthesis

Grignard reagents are among the most frequently used reagents in organic synthesis. They react with a wide variety of substrates; however, in this section, we are concerned only with those reactions that produce alcohols. Notice that in a reaction involving a Grignard reagent, not only does the functional group get changed, but the number of carbon atoms present also changes. This fact provides us with a useful method for ascending a homologous series. For example:

synthesizing ethanol from methanol with a Grignard reagent

One important route for producing an alcohol from a Grignard reagent has been omitted from the discussion in the reading. It involves the reaction of the Grignard reagent with ethylene oxide to produce a primary alcohol containing two more carbon atoms than the original Grignard reagent.

Grignard reagent with ethylene oxide to produce a primary alcohol

As mentioned in the reading, both organolithium and Grignard reagents are good nucleophiles. They also act as strong bases in the presence of acidic protons such as −CO₂H, −OH, −SH, −NH and terminal alkyne groups. Not only do acidic protons interfere with the nucleophilic attack on the carbonyl of these organometallic reagents, if the starting materials possess any acidic protons, reagents cannot be generated in the first place. They are also the reason these reactions must be carried out in a water‑free environment.

Another limitation of preparing Grignard and organolithium reagents is that they cannot already contain a carbonyl group (or other electrophilic multiple bonds like C$\ce{=}$N C$\ce{#}$N, N$\ce{=}$O S$\ce{=}$O) because it would simply react with itself.

A summary of the methods used to prepare alcohols from Grignard reagents is provided below.

summary of alcohols prepared from Grignard reagents and different starting compounds

Many of these alcohols can be converted to an alkene, by heating with an acid such as H₂SO₄ or H₃PO₄., via an E1 elimination (see section 9.9.). However, this can often give mixtures of isomeric alkene products with the double bond at different positions. Therefore, when the target product of a C-C bond forming reaction is an alkene, it is usually better to use a Wittig reaction instead, because this will form the new double bond unambiguously at one position.

Using the aldol reaction in synthesis

Objectives

After completing this section, you should be able to identify the aldehyde or ketone and other necessary reagents that should be used to prepare a given enone by an aldol condensation.

Aldol reactions are excellent methods for the synthesis of many enones or beta hydroxy carbonyls. Because of this, being able to predict when an aldol reaction might be used in a synthesis in an important skill. This accomplished by mentally breaking apart the target molecule and then considering what the starting materials might be.

Fragments which are easily made by an aldol reaction

Alpha,beta-unsaturated carbonyl compounds, such as the enone shown above, are useful for performing conjugate addition reactions, as was covered in section 20.7.

Synthesis using nucleophilic addition chemistry. Authored by: Martin A. Walker. Provided by: SUNY Potsdam. Project: Organic chemistry: An open textbook. License: CC BY-SA: Attribution-ShareAlike

Organic Chemistry With a Biological Emphasis . Authored by: Tim Soderberg. Located at: https://chem.libretexts.org/Textbook_Maps/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_(Soderberg)/13%3A_Reactions_with_stabilized_carbanion_intermediates_I/13.6%3A_Synthetic_parallel_-_carbon_nucleophiles_in_the_lab#13.6D:_Grignard.2C_Gilman.2C_and_organolithiuim_reagents. Project: Chemistry LibreTexts. License: CC BY-NC-SA: Attribution-NonCommercial-ShareAlike