Strategies for Synthesis and Retrosynthesis | Organic Chemistry 1

Retrosynthetic strategies are studied in this chapter: protecting groups, protection and deprotection, alcohol protecting groups, carbonyl protecting groups, retrosynthetic analysis, retrosynthetic strategies

Protection - Deprotection

A molecule usually has more than one chemical function. In order to obtain chemoselectivity during a reaction, the chemical functions that may react to form side products must be protected. At the end of the desired reaction, a deprotection step allows to regenerate the initial chemical function

Protecting group:

A blocking group that renders a reactive functional group unreactive so that it does not interfere with another reaction

Protection - Deprotection:

  • Protection: the reaction that blocks a reactive functional group with a protecting group
  • Deprotection: a reaction that removes a protecting group, regenerating a functional group

Alcohol Protecting Groups

Conversion to silyl ether

  • Protection: the OH group is converted into an silyl ether using silylchloride in a basic solvent (imidazole, pyridine ...). The most widely used silyl ether protecting group is the tert-butyldimethylsilyl ether, abbreviated as TBDMS ether
  • Deprotection: the protecting group is removed with a fluoride salt


Conversion to ether

  • Protection: the OH group is converted into an ether using another alcohol under acidic conditions
  • Deprotection: the protecting group is removed by an acid or a base


Grignard reaction on unprotected and protected 4-hydroxycyclohexan-1-one:



Carbonyl Protecting Groups

Conversion to acetal or ketal

  • Protection: the aldehyde or ketone is converted respectively into acetal or ketal with a diol under acidic conditions
  • Deprotection: the protecting group is removed by an acid

Retrosynthetic Analysis

Retrosynthetic analysis:

Working backwards from a product to determine the starting material from which it is made

Retrosynthetic process:

  • Count the number of carbons in the product and reagents, and determine the disconnects you need
  • Find the immediate precursor(s), keeping in mind the compounds you have in your toolbox
  • At this point, you have 2 different possibilities:
    - formation of a carbon-carbon bond
    - the synthesis of a particular chemical function by deprotonation, substitution, elimination, oxidation or reduction reactions

Follow the same process with the precursors until you get to the starting reagents


Strategy to synthesize heptan-3-ol, using propanal, butan-1-ol and any inorganic reagents

Retrosynthetic analysis:

  • 1st goal: formation of a carbon-carbon bond between the blue and the green alkyl chains ⇒ organometallics + carbonyls
  • 2nd goal: chemical function modification to form organometallics starting from alkyl halide
  • 3rd goal: chemical function modification to form alkyl halide starting from butan-1-ol

Proposed Synthesis:

Retrosynthesis Strategies

How to form a carbon-carbon bond

  • Reaction of an aldehyde or ketone with a Grignard or organolithium reagent (chapter 8)
  • Reaction of an alkyl halide with a Gilman reagent (chapter 8)
  • Reaction of an organometallic reagent with an epoxide (chapter 9)

How to synthesize particular functional groups


  • Nucleophilic substitution of an alkyl halide with HO- or H2O (chapter 6)
  • Reduction of an aldehyde with NaBH4 (chapter 8)
  • Reduction of a ketone with LiAlH4 (chapter 8)
  • Reaction of an aldehyde or ketone with a Grignard or organolithium reagent (chapter 8)
  • Reaction of an organometallic reagent with an epoxide (chapter 9)


  • Oxidation of a primary alcohol with PCC (chapter 8)


  • β Elimination of an alkyl halide or an alkyl tosylate with base (chapter 7)
  • Dehydration of an alcohol with acid (chapter 9)
  • Dehydration of an alcohol using POCl3 and pyridine (chapter 9)

Alkyl halides:

  • Radical halogenation of an alkane with X2 (chapter 3)
  • Reaction of an alcohol with SOCl2 or PBr3 (chapter 9)
  • Reaction of an alcohol with HX (chapter 9)

Carboxylic acids:

  • Oxidation of a primary alcohol with Na2Cr2O7 (chapter 8)


  • Intramolecular SN2 reaction of a haloalcohol using base (chapter 8)


  • Williamson ether synthesis: SN2 reaction of an alkyl halide with an alkoxide (chapter 8)
  • Reaction of an alkyl tosylate with an alkoxide


  • Oxidation of a secondary alcohol with PCC or Na2Cr2O7 (chapter 8)

Check your knowledge about this Chapter

Common strategies for the synthesis of complex molecules include retrosynthetic analysis, the use of protecting groups, and functional group transformations: 

  • Retrosynthetic analysis involves working backwards from the target molecule to simpler precursors, identifying key bonds or functional groups that can be constructed in a stepwise manner.
  • Protecting groups are used to temporarily mask reactive functional groups during synthesis to prevent unwanted reactions, and can be selectively removed once they have served their purpose.
  • Functional group transformations change one functional group into another, providing diversity and complexity to the molecular structure.

Retrosynthetic analysis is a strategy used by chemists to plan the synthesis of complex organic molecules by breaking them down into simpler precursor structures. This process involves working backwards from the target molecule, identifying strategic bonds to "disconnect" in order to reveal simpler structures that can be commercially available or more easily synthesized. The method allows chemists to visualize a synthetic route as a sequence of individual transformations, each of which is achievable using known reactions. It simplifies the approach to creating complex molecules by focusing on one step at a time, often revealing multiple pathways to synthesize the desired compound, which can then be evaluated for factors such as cost, efficiency, and selectivity.

Disconnections in retrosynthesis are theoretical breaks made in the structure of a complex molecule to simplify it into smaller, more manageable fragments for chemical synthesis. These strategic breaks are typically made at bonds that can be formed via known and reliable chemical reactions. Identifying disconnections involves recognizing functional groups and familiar patterns within molecules that suggest possible synthetic routes, often using "synthons" which are idealized fragments representing reactivity patterns. Chemists consider factors such as the feasibility of the synthetic route, the availability of starting materials, and the overall yield and efficiency to identify the best disconnections for a targeted synthesis.

Protecting groups are chemical functionalities that are temporarily added to reactive sites in molecules to prevent unwanted reactions during a synthesis. They are particularly useful for protecting functional groups such as alcohols, amines, or carbonyls that might otherwise react under the conditions required for a different transformation elsewhere in the molecule.

Their importance lies in their ability to simplify complex organic syntheses, allowing chemists to carry out reactions step-wise and selectively. After the desired transformation is complete, protecting groups can be removed, or 'deprotected', to reveal the original functional groups, now unaltered by the synthetic steps that were necessary for the overall synthesis.

Protecting groups in a synthetic sequence can have both positive and negative effects on the overall yield: 

  • They are crucial when there are multiple reactive sites in a molecule, as they can shield a particular functional group from unnecessary reactions during a step in the synthesis. The use of protecting groups can improve the selectivity of the reaction and help obtain the desired product in higher purity.
  • However, each additional step required to add and then remove a protecting group introduces further opportunities for side reactions and loss of material, potentially decreasing the overall yield.

The strategic selection and efficient introduction/removal of protecting groups are therefore vital in designing an effective synthetic pathway.

  • Orthogonality in protection/deprotection strategies allows chemists to selectively add or remove protecting groups without affecting others within the same molecule. This is crucial when multiple protective groups are necessary due to the molecule's complexity; each group must be removable under different, non-overlapping conditions to avoid undesired side reactions.
  • Chemoselectivity is similarly vital because it ensures that the reaction affects only the desired functional group while leaving others intact. This selectivity is especially important in multifunctional molecules where different functional groups can react under similar conditions, and controlling the reaction outcome is essential for the correct modification or synthesis of the target molecule.

In organic synthesis, common alcohol protecting groups include TBDMS and TMS for silyl ethers, MOM and Bn for ethers, and Troc, Boc, and PMB for various applications. These protecting groups provide stability and are selectively removed during deprotection steps, typically with fluoride for silyl ethers and acid for ethers. The choice depends on factors such as stability under conditions, ease of installation, and compatibility with other functional groups in the molecule.

The conversion to silyl ethers involves reacting hydroxyl groups with silylchloride in a basic solvent such as imidazole or pyridine. This forms the silyl ether, protecting the hydroxyl group from reactivity with other functional groups.

TBDMS ether is widely used due to its stability under various conditions. It provides effective protection, and its deprotection can be achieved selectively with fluoride sources.

Hydroxyl groups are protected by reacting with another alcohol under acidic conditions, forming ethers. Deprotection of ethers in organic synthesis commonly involves acidic or basic conditions, hydrogenolysis with a metal catalyst, metal-ammonia reduction for specific protecting groups, and photolysis using ultraviolet light. The choice of deprotection method is tailored to the protecting group and the desired selectivity in removing the ether linkage during the synthesis process.

Carbonyl protecting groups are used to temporarily mask a carbonyl functional group so that it does not participate in unwanted side reactions during multi-step synthesis. For example, a ketone or aldehyde can be converted into an acetal or ketal, which are unreactive to conditions that might affect the free carbonyl group, like reduction or Grignard reactions. After other reactions are carried out, the protecting group can be removed to reveal the original carbonyl functionality, usually under mild acidic conditions that do not interfere with the newly formed chemical bonds in the molecule.