Lena Savoie
Connecting two molecules with an alcohol group is a process that has been extensively studied in the field of chemistry, particularly in the context of synthetic chemistry and drug discovery. This process, known as chemoselective hydroxyl group transformation, involves selectively reacting one functional group while in the presence of others. While this task may seem straightforward, it presents a unique set of challenges due to the need to target specific hydroxyl moieties. The successful linkage of two molecular fragments through selective arylation or acylation of the hydroxyl group can lead to the formation of valuable compounds with potential applications in medicine and biochemistry.
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What You'll Learn
Chemoselective hydroxyl group transformation
The chemoselective transformation of the hydroxyl group has been utilised in various applications, such as the synthesis of complex natural product derivatives, the reaction of tyrosine residues in proteins, and the isolation of natural products. It is also essential in the mechanism of action of many drugs.
Several methods have been developed to selectively target the hydroxyl group. One approach is through direct conjugation reactions, oxidation, and the generation of a leaving group (e.g., Cl, tosyl). Additionally, the transformation to an alternative chemical handle, such as azide or thiol, is also employed. Selective O- or N-arylation can be achieved using specific catalysts; copper-mediated catalysis favours O-arylation, while palladium yields N-arylation products.
Furthermore, chemoselective hydroxyl group transformations can be electrochemically promoted, utilising TBAF as an electrolyte and hydrogen-bonding additive. This method offers advantages such as high chemo- and site-selectivity and excellent conversion under mild and neutral conditions. It enables the labelling of tyrosine residues and the tagging of proteins and cyclic peptide drugs with anthranilic acid derivatives.
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![The application of Victor Meyer's esterification law to neighboring xylic acid and its reduced derivatives / by Walter John Richard Heinekamp. 1920 [Leather Bound]](https://m.media-amazon.com/images/I/61IX47b4r9L._AC_UY218_.jpg)
Selective arylation and acylation
The selective reaction of one functional group in the presence of others is a challenging task. Chemoselectivity is of utmost importance in synthetic chemistry, and the hydroxyl group is a prevalent functional group in many biologically and industrially relevant molecules.
A significant amount of effort has been dedicated to developing strategies for the selective reaction of an alcohol group in the presence of an amine group. This is due to the abundance of compounds containing both functional groups and the relatively low nucleophilicity of the hydroxyl group. Several synthetic strategies have been devised to selectively arylate and acylate the hydroxyl group while circumventing the protection and subsequent unmasking of the amine group.
Ullmann-type couplings, for instance, have been widely used to form C-C, C-N, and C-O bonds and can be tuned for either hydroxyl or amine selectivity. Additionally, modified 4-(N,N'-dimethylamino)pyridine (DMAP)- and peptide-based catalysts have been explored to selectively functionalize the secondary hydroxyl groups of carbohydrates.
Furthermore, transition-metal-catalysed arylation and alkylation reactions have been employed to directly harness alcohols for organic synthesis. For example, copper-catalysed dynamic kinetic asymmetric C−O cross-coupling allows access to chiral aryl oxime ethers and diaryl ethers. Additionally, dual-relay Rh-/Pd-catalysis enables β-C(sp3)–H arylation of α-substituted amines.
In terms of acylation, an indium triiodide-catalysed transesterification process has been used to achieve the highly selective acylation of primary OH groups in the presence of secondary and phenolic OH groups. This method has also been applied to the selective acylation of a primary NH2 group in the presence of secondary NH and primary OH groups. Other simple and convenient methods for the selective acylation of primary alcohols in the presence of secondary alcohols have also been reported, employing catalysts such as N-methyl-2-phenylimidazole (Ph-NMI) or 2-phenylimidazo [2,1-b]benzothiazoles (Ph-IBT).
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Dehydration and oxidation
The dehydration of alcohols to form alkenes is relatively well-understood in both thermodynamic and mechanistic terms at hydrothermal and ambient conditions. At ambient conditions, the addition of water to an alkene to form an alcohol is favored due to the formation of a stronger σ-bond at the expense of a weaker π-bond. However, Brønsted or Lewis acid catalysis is required for this reaction. Under hydrothermal conditions, water acts as the solvent and provides the catalyst, and no additional reagents are required. This makes hydrothermal dehydration an attractive prospect in the context of green chemistry.
The E1 mechanism of dehydration is observed in secondary and tertiary alcohols. In this mechanism, the secondary and tertiary –OH protonate to form alkyloxonium ions. The ion then leaves, forming a carbocation as the reaction intermediate. A water molecule then abstracts a proton from an adjacent carbon to form a double bond. The alkene formed depends on which proton is abstracted, with the more substituted alkene being the major product due to its higher stability.
The E2 mechanism of dehydration is observed in 3º-alcohols under relatively non-acidic conditions. This mechanism can be accomplished by treating the alcohol with phosphorous oxychloride (POCl3) in pyridine. This method can also be applied to hindered 2º-alcohols. However, for unhindered and 1º-alcohols, an SN2 chloride ion substitution of the chlorophosphate intermediate competes with elimination.
In the oxidation reaction of alcohol, two hydrogen atoms are removed from the alcohol molecule, one from the OH group and the other from the carbon atom bearing the OH group. This reaction can be carried out in a laboratory setting with chemical oxidizing agents such as potassium dichromate. The oxidation of primary alcohols yields aldehyde as an intermediate and carboxylic acid as the final product. The oxidation of secondary alcohols produces ketone, which cannot be further oxidized as it would require breaking a C–C bond, requiring too much energy. Tertiary alcohols cannot be oxidized for the same reason.
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Esterification
The Fischer esterification reaction involves heating a mixture of carboxylic acids and an excess amount of corresponding alcohols in the presence of a catalyst. The reaction achieves equilibrium after a certain time, governed by process kinetics and thermodynamics. However, the reaction does not reach completion, compromising the product yield. This is due to the slow rate of reaction and low overall conversion, presenting challenges in achieving a cost-effective and environmentally friendly process.
To address these challenges, it is crucial to analyse the current status of esterification technologies and explore emerging solutions. One approach is to focus on the chemistry and kinetics of the reaction, its optimization, and the factors influencing its productivity. Additionally, the role of enzymes and acid catalysts in accelerating the reaction rate is significant, along with their advantages and disadvantages.
The esterification process can be enhanced by improving the rate of reaction and overall conversion. This can be achieved through non-catalytic thermal processes, where reactions are conducted at high temperatures and pressures without catalysts. In these processes, alcohol is heated to its subcritical or supercritical temperature, ensuring fast reactivity between the reaction components.
Furthermore, the quality of chemicals used in the esterification method is vital. Advanced specialty chemicals are required to ensure the desired outcome. Synthetic polymers and organic chemical molecules are examples of products that can be synthesized through esterification.
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Ullmann-type couplings
One example of an Ullmann-type coupling reaction is the formation of C-O bonds, catalysed by an air-stable copper(I)-bipyridyl complex. Another example is the synthesis of N-aryl hydrazides through the copper-catalysed coupling of hydrazides with aryl iodides. This reaction has been studied by researchers such as M. Wolter, A. Klapars, and S.L. Buchwald.
The use of bidentate ligands, such as oxalic diamides and tert-butoxide, has improved the performance of Ullmann-type couplings, allowing for milder reaction conditions. This has enabled the inclusion of sensitive functional groups and the coupling of less reactive aryl chlorides.
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Frequently asked questions
One simple reaction to connect two molecules with an alcohol group is to esterify. However, hydrolysis can occur.
Yes, the Williamson ether synthesis can be used to prepare simple alkyl ethers.
The Williamson ether synthesis allows for the retention of the original oxygen atom in the product.
Yes, if retention of the original oxygen atom is not necessary, making it a better leaving group can permit substitution.
Yes, another option is the reaction of the alcohol group with isocyanates or isothiocyanates.
