In this article we will talk about alcohols and their properties. We will also cover the different types of alcohols reactions that can occur and the products that can be derived from them.
Topics Covered in Other Articles
- Redox Reactions & Oxidation Reduction
- Aldehyde Functional Group
- Alcohol Functional Group
- Carboxylic Acid Functional Group
- SN1 Reaction
Conversion of alcohols into Alkyl halides
There are several methods to convert an alcohol into an alkyl halide, including hydrohalogenation, reaction with phosphorus tribromide, and reaction with thionyl chloride. Let’s look at each of them one at a time!
Alcohols may be converted into alkyl halides through hydrohalogenation. In this context, halide ions serve as potent nucleophiles, surpassing the nucleophilic strength of water. Due to the high concentration of halide ions, most carbocations formed during the reaction readily react with a halide ion, forming a more stable species—the alkyl halide product.
This process predominantly follows an SN1 mechanism. In this mechanism, halide ions are present in high concentrations, enabling them to react with the carbocations formed during the process. This results in the formation of a more stable species—the alkyl halide products.
The overall reaction involves nucleophilic substitution, where halide ions replace the hydroxyl group in the alcohol, resulting in the formation of alkyl halides.
Phosphorus tribromide (PBr3)
Phosphorus tribromide (PBr3) converts alcohols to alkyl bromides. Unlike the reaction with HBr, this transformation does not involve the formation of a carbocation and typically proceeds without rearrangement of the carbon skeleton, especially when conducted at temperatures below 0 °C.
The reaction proceeds through the interaction of PBr3 with the alcohol, resulting in the displacement of the hydroxyl group by a bromine atom.
It’s important to highlight that an intermediate called HOPBr2 is generated during the reaction. Interestingly, this intermediate can react with two more equivalents of the alcohol, resulting in the conversion of three moles of alcohol to alkyl bromides using just one mole of phosphorus tribromide. This method is valuable in organic synthesis for adding bromine substituents without forming carbocation intermediates. It is especially useful when you want to keep the original carbon structure intact.
Thionyl chloride (SOCl2)
The reaction of alcohols with thionyl chloride (SOCl2) is a common method for converting primary and secondary alcohols into alkyl chlorides. Typically, this reaction proceeds without rearrangement.
The mechanism involves nucleophilic addition–elimination by a chloride ion on a highly reactive intermediate: a protonated acyl chlorosulfite.
The use of a tertiary amine in the reaction helps by reacting with the hydrogen chloride produced, preventing it from inhibiting the reaction. The overall result is the conversion of the alcohol to an alkyl chloride, with the thionyl chloride serving as a dehydrating and chlorinating reagent. This method efficiently converts alcohols to alkyl chlorides by utilizing chloride ions as leaving groups, ensuring the reaction’s completion.
Leaving Groups derivatives of Alcohols
We can transform the alcohol functional group into an effective leaving group by creating a sulfonate ester derivative. The primary sulfonate esters employed for this purpose are methanesulfonate esters, commonly known as “mesylates,” and p-toluenesulfonate esters, referred to as “tosylates.”
Mesylates and Tosylates
In organic synthesis, the conversion of alcohols to mesylates and tosylates is a common strategy for enhancing reactivity, especially in nucleophilic substitution reactions. Alcohols, which are typically nonreactive due to the poor leaving group ability, can be made into better leaving groups by reacting them with mesyl chloride or tosyl chloride in the presence of a base.
This process involves the deprotonation of the alcohol and the subsequent reaction with the respective sulfonate chlorides, resulting in the formation of mesylates (MsO) or tosylates (TsO). The resulting mesylate or tosylate serves as an excellent leaving group, facilitating nucleophilic substitution reactions.
Silyl Ether Protecting Groups
Protecting groups serve as chemical modifications that shield hydroxyl groups in organic compounds from acid-base reactions. One of the commonly employed silyl ether protecting groups is the tert-butyldimethylsilyl (TBS) ether group, denoted as tBS−o−R. Other variations such as trimethylsilyl (TMS), and triisopropylsilyl (TIPS) can also be utilized.
The addition of a TBS group is achieved by allowing the alcohol to react with tert-butyldimethylsilyl chloride in the presence of an aromatic amine acting as a base, like imidazole or pyridine. This conversion of an alcohol to a silyl ether not only protects the hydroxyl group from acid–base reactions but also imparts increased volatility to the compound.
Alcohols can undergo elimination reactions to form alkenes. This reaction requires heat and a strong acid to proceed.
Primary alcohols are the most challenging to dehydrate. This process typically follows an E2 mechanism, and temperatures of as high as 180 °C can be required.
Secondary alcohols generally undergo dehydration through an E1 mechanism. Compared to primary alcohols, they usually require milder conditions. For example, cyclohexanol can be dehydrated in 85% phosphoric acid at temperatures ranging from 165 to 170 °C.
Tertiary alcohols exhibit the highest susceptibility to dehydration and this reaction typically proceeds under mild conditions. For example, dehydration of tert-butyl alcohol can be accomplished using 20% aqueous sulfuric acid at temperatures as low as 85 °C. The enhanced ease of dehydration observed in tertiary alcohols stems from the stability of the resulting carbocation intermediate.
The Pinacol Rearrangement is a reaction in which a fully substituted 1,2-diol (vicinal diol) undergoes an acid-catalyzed elimination of water to yield a carbonyl compound. One example of this reaction is the conversion of pinacol, a 1,2-diol, to t-butyl methyl ketone.
Protonation of a hydroxyl group on the 1,2-diol substrate initiates the reaction, creating a water leaving group.
Deprotonation leads to cleavage of the C-O bond and formation of the carbocation. At this step, the carbocation resonance structure containing the carbonyl group is most stable. This thermodynamic driving force causes the carbocation to rearrange its structure via a 1,2-alkyl shift. The alkyl/aryl group migrates to the carbocation center, creating a new carbon-carbon double bond and generating the carbonyl group. The relative stability or migratory aptitude of the substituents determines the position of migration.
Hydrogen is generally the most migratory, followed by phenyl and then alkyl groups in order of decreasing migratory ability. This allows for regioselective control of the carbocation rearrangement based on the substrate structure. Once rearranged, the carbocation intermediate adopts a new resonance form with the carbonyl group delocalized. Protonation then occurs, disrupting the conjugate system and yielding the carbonyl compound product.
The oxidation of primary and secondary alcohols typically follows a common mechanistic pathway when specific reagents are employed. These reagents temporarily introduce a leaving group on the hydroxyl oxygen in the reaction.
The process involves the loss of a hydrogen from the hydroxyl carbon, coupled with the departure of the leaving group from the oxygen, resulting in an elimination that forms the π bond in a carbonyl group (C=O). This formation of the carbonyl double bond occurs analogously to the creation of a double bond in an alkene through an elimination reaction.
When you oxidize secondary alcohols, they usually turn into ketones. The process usually stops at the ketone stage because going further would mean breaking a carbon–carbon bond.
Oxidation using PCC Pyridinium Chlorochromate
The oxidation of primary alcohols with pyridinium chlorochromate (PCC) is a selective and mild oxidation process that typically results in the conversion of primary alcohols to aldehydes. The reaction proceeds through a two-step mechanism, involving the formation of a chromate ester intermediate.
Pyridinium chlorochromate (PCC) is prepared by combining pyridine (C6H5N), hydrochloric acid (HCl), and chromium trioxide (CrO3), resulting in the formation of a chromium(VI) salt. One notable application of PCC is in the oxidation of primary alcohols to aldehydes. Its solubility in dichloromethane allows for reactions that exclude water, preventing the formation of aldehyde hydrates. The distinctive feature of PCC (pyridinium chlorochromate) in comparison to other reagents, like the Jones reagent, is its selective oxidation of primary alcohols to carboxylic acids, operating in a non-aqueous environment.
Swern oxidation is a method for converting primary alcohols to aldehydes and secondary alcohols to ketones. It utilizes a complex formed between dimethyl sulfoxide (DMSO) and oxalyl chloride. The alcohol reacts with this complex, leading to the formation of an alkoxy sulfonium ion intermediate.
A series of rearrangement and elimination steps occur, resulting in the oxidation of the alcohol to an aldehyde or ketone. We use anhydrous conditions to conduct this reaction to prevent overoxidation of primary alcohols to carboxylic acids, also we employ a workup step with a mild reducing agent to isolate the desired product.
Primary alcohols to Carboxylic Acids
Oxidation using Periodic acid
Aqueous periodic acid (HIO4) is a useful chemical for breaking certain compounds that have hydroxyl groups on neighboring atoms. This reaction, known as oxidative cleavage, breaks carbon–carbon bonds and produces carbonyl compounds like aldehydes, ketones, or acids, depending on the starting material. Adjacent carbon atoms with hydroxyl groups transform into carbonyl functionalities in a cyclic intermediate during the hypothesized process.
In this process, the aqueous periodic acid reacts with a compound that has adjacent hydroxyl groups on its carbon atoms. Periodic acid breaks neighboring carbon-carbon bonds near hydroxyl groups, resulting in the formation of carbonyl compounds.
Oxidation using Potassium permanganate
In this oxidation of primary alcohols to form the corresponding carboxylic acids we utilize potassium permanganate (KMnO4). We conduct this reaction in a basic aqueous solution, causing the precipitation of manganese dioxide (MnO2) as the oxidation progresses.
Dess-Martin periodinane (DMP oxidation)
Industry commonly use the Dess-Martin oxidation as a method in organic synthesis, employing a compound called Dess-Martin periodinane (DMP) as the primary oxidizing agent. We prepare DMP through a two-step synthesis starting from 2-iodobenzoic acid. Compared to traditional chromium-based oxidation methods, the Dess-Martin oxidation offers several advantages.
Firstly, it operates under mild reaction conditions, avoiding the need for harsh conditions that can potentially damage or degrade sensitive functional groups in organic molecules.
In the oxidation of 2-propanol using Dess-Martin periodinane (DMP), an acid activates DMP to form a hypervalent iodine species. The alcohol undergoes nucleophilic attack on the active oxidant, forming an iodoalkane intermediate, then it is Deprotonated and it eliminates the iodine to generate an alkoxide ion, which further eliminates iodine to yield the desired ketone.
Lastly, the ketone is protonated by the acid, regenerating the active oxidant, and ultimately forming the final ketone product.
Oxidation using Chromic acid
Oxidations involving chromium(VI) reagents, such as H2CrO4, are commonly employed for their simplicity and effectiveness, although chromium(VI) itself poses carcinogenic and environmental hazards. In particular, methods like the Swern oxidation have gained importance due to safety concerns associated with chromium.
To prepare the Jones reagent, one can add CrO3 or Na2CrO4 to aqueous sulfuric acid. This reagent, which is a renowned source of H2CrO4, finds application by adding it to solutions of alcohols or aldehydes in oxidation-resistant solvents like acetone or acetic acid.
Oxidation of Tertiary alcohols
In the case of tertiary alcohols even though they readily form chromate esters, the resulting ester lacks a hydrogen that can be removed, preventing any oxidation from occurring.
If you want to have a further reading on the oxidation of alcohols check this article!