Question

Following is a retrosynthetic scheme for the synthesis of cis-3-penten-2-ol. Write a synthesis for this compound from acetylene, acetaldehyde, and iodomethane.

Short answer

Question: Outline the four-step synthesis pathway for cis-3-penten-2-ol using acetylene, acetaldehyde, and iodomethane as starting materials. Answer: The synthesis pathway involves the following steps: 1. Alkyne hydroboration-oxidation: Acetylene reacts with borane reagent and is then treated with hydrogen peroxide and sodium hydroxide to form 1-propen-1-al. 2. Grignard reagent formation: Iodomethane reacts with magnesium metal to form a methylmagnesium iodide Grignard reagent. 3. Nucleophilic addition: The Grignard reagent (CH3MgI) reacts with the carbonyl group of 1-propen-1-al, adding a methyl group and yielding an alkoxide. 4. Protonation: The alkoxide formed in Step 3 is protonated by adding an aqueous acidic solution, replacing the MgI group with a hydroxyl (OH) group and yielding cis-3-penten-2-ol as the final product.

Step-by-step solution

Alkyne hydroboration-oxidation

The first step is to convert acetylene (ethyne) into an aldehyde using hydroboration-oxidation. This involves adding a borane reagent (e.g., BH3) to the triple bond and then treating it with hydrogen peroxide and sodium hydroxide. The product is 1-propen-1-al (propenal). Acetylene + BH3 + H2O2 + NaOH → 1-propen-1-al

Grignard reagent formation

In this step, we form a Grignard reagent using iodomethane and magnesium metal. Grignard reagent is a highly reactive organometallic compound that facilitates the formation of new carbon-carbon bonds. Iodomethane reacts with magnesium to form a methylmagnesium iodide Grignard reagent. Iodomethane + Mg → CH3MgI

Nucleophilic addition of Grignard reagent

Now, we carry out a nucleophilic addition of the Grignard reagent (CH3MgI) to the carbonyl group of the 1-propen-1-al formed in Step 1. This adds a methyl group to the carbonyl carbon, yielding an alkoxide. 1-propen-1-al + CH3MgI → 1,1-dimethyl-1-propen-2-olate MgI

Protonation of alkoxide

To obtain the desired alcohol cis-3-penten-2-ol, we protonate the alkoxide formed in Step 3 by adding an aqueous acidic solution such as aqueous HCl. This will replace the MgI group with a hydroxyl (OH) group, giving the final product. 1,1-dimethyl-1-propen-2-olate MgI + HCl → cis-3-penten-2-ol + MgClI In conclusion, the synthesis of cis-3-penten-2-ol from acetylene, acetaldehyde, and iodomethane can be accomplished in four steps: alkyne hydroboration-oxidation, Grignard reagent formation, nucleophilic addition, and protonation.

Key concepts

Alkyne Hydroboration-Oxidation

Alkyne hydroboration-oxidation is a two-step reaction process that converts alkynes to aldehydes or ketones. In organic synthesis, this method is especially valuable for its mechanism, which involves the addition of a borane (BH₃) to the triple bond of an alkyne. This results in an organoborane intermediate.

The subsequent oxidation step typically employs hydrogen peroxide (H_2O_2) and a strong base like sodium hydroxide (NaOH). This transformation turns the boron-containing compound into an alcohol, which immediately tautomerizes to the corresponding aldehyde or ketone. The overall process is stereoselective, typically leading to the anti-Markovnikov product—meaning that the substituent attaches to the less substituted carbon of the triple bond. This feature is pivotal when designing retrosynthetic pathways for complex molecules like cis-3-penten-2-ol from simple precursors such as acetylene.

Grignard Reagent Formation

Grignard reagents are crucial tools in organic chemistry, pivotal for creating carbon-carbon bonds. They form when alkyl or aryl halides react with magnesium metal in anhydrous ether. The general structure of a Grignard reagent is R-Mg-X, where R is an alkyl or aryl group and X is a halide.

The formation of the Grignard reagent is critical because it represents the nucleophilic species, ready to attack electrophilic carbons such as those found in carbonyl groups. The reaction involves breaking the carbon-halogen bond and forming a carbon-metal bond. A key requirement for successful Grignard reagent formation is the complete absence of moisture since even trace amounts of water can destroy the reagent. Safety measures are also important since reactions involving organometallics can be highly exothermic.

Nucleophilic Addition

Nucleophilic addition is a fundamental process in synthesis where a nucleophile, such as a Grignard reagent, donates a pair of electrons to an electrophile, forming a new chemical bond. Aldehydes and ketones, with their polarized carbonyl groups, are prime targets for nucleophilic attack because of the partial positive charge carried by the carbonyl carbon.

During the nucleophilic addition to a carbonyl group, the nucleophile attacks the electrophilic carbon, leading to the formation of a tetrahedral intermediate. This intermediate, in the case of aldehyde reactions with a Grignard reagent, results in an alkoxide with a new alkyl group attached to the former carbonyl carbon. The reaction proceeds with the opening of the carbonyl's planar structure and the eventual displacement of the double-bonded oxygen to a single-bonded oxygen atom.

Protonation of Alkoxide

The protonation of alkoxides to form alcohols is a fundamental step in organic chemistry. Alkoxides are the oxygen analogs of alkyl anions and are potent bases and nucleophiles. In the context of organic synthesis, the alkoxide is often formed through the nucleophilic addition of organometallic reagents to carbonyl groups.

Protonation is a straightforward acid-base reaction where an acid donates a proton (a hydrogen ion, H⁺) to a base (here, the alkoxide). By adding an appropriate acidic solution like aqueous hydrochloric acid (HCl), the negatively charged oxygen in the alkoxide grabs a proton, forming the alcohol and regenerating the magnesium halide salt. This final deposition of the hydroxyl group completes the transformation of functional groups, culminating in the synthesis of complex organic molecules like cis-3-penten-2-ol.