Appel Reaction

What Is Appel Reaction?

Triphenylphosphine and tetrahalogenated (chlorine or bromide) carbon react with alcohols (generally primary alcohols and secondary alcohols) to convert alcohols into halogenated hydrocarbons under mild and almost neutral conditions. This reaction is particularly valuable due to its ability to be carried out under neutral conditions, making it suitable for the synthesis of acid- and base-sensitive alcohols. The high yields observed in this transformation contribute to the reaction's widespread application in synthetic organic chemistry.

Lee's group first reported the Ph₃P+CCl₄ system, and Appel systematically studied the reaction intermediates, so the reaction is also called the Appel-Lee reaction. Electrophilic reagents that match triphenylphosphine can be extended to reagents containing electrophilic halide ions (Br₂, Cl₂, C₂Cl₆).

Fig 1. Appel reaction and its mechanism. [1]

Mechanism of Appel Reaction

The Appel Reaction proceeds through a series of steps, starting with the activation of triphenylphosphine by reaction with a tetrahalomethane, such as carbon tetrachloride (CCl₄) or carbon tetrabromide (CBr₄). This results in the formation of an oxyphosphonium intermediate through the attack of the alcohol oxygen at phosphorus, followed by the transformation of the oxygen into a leaving group. Ultimately, an SN₂ displacement by halide takes place, leading to the inversion of configuration if the carbon is asymmetric.

Stereoselectivity of Appel Reaction

Alcohols in different stereo environments show different reactivity, so chemically selective halogenation can be carried out by controlling the reaction conditions. Recently, Jan Tönjes et al. reported a new method for catalyzing the Appel reaction, which achieved the conversion of 26 alcohols and 9 epoxides containing various functional groups into the corresponding chlorides and dichlorides with yields up to 97%, enantiomeric specificity up to >99%, and enantiomeric ratios up to >99:1. [2]

Fig 2. Stereocatalysis of Appel reaction.

Application Examples of Appel Reaction

• Example 1: The Appel reaction conditions are mild and widely used in the synthesis of natural products, such as insect pheromones, (-)-heptemerone B and (-)-bipinnatin J. In addition, the halogenation of allylic alcohols generally does not undergo double bond migration, as shown by the conversion of compound 22 to compound 23 in the total synthetic route of (-)-bipinnatin J. [3]
• Example 2: Mild biosynthetic dehydration of endoperoxides to generate multiply substituted electron-rich furans using Appel reaction conditions. This method is metal- and acid-free and can be achieved under redox-neutral conditions. It is applicable to a range of aryl- and alkyl-substituted endoperoxides and is tolerant of functional groups. In addition, this method was used to achieve an efficient total synthesis of furan fatty acid (FFA) F₅. [4]
• Example 3: Appel reaction can also convert carboxylic acids into haloimines. Yong-Hua Yang et al. reported that cyclopropane amides can be converted into γ-lactams under Appel reaction conditions, and the reaction intermediate is a haloimine. In the presence of 2 equivalents of PPh₃ and 1 equivalent of CX₄, the corresponding imino halide activated cyclopropane amide (monoactivated cyclopropane) was successfully prepared in situ, and the ring expansion product (N-substituted pyrrolidin-2-one) was obtained in high yield. [5]

Fig 3. Synthetic examples via Appel reaction.

Related Products

CAS No.	Structure	Product
58079-51-9		TRIPHENYLPHOSPHINE
501-94-0		2-(4-Hydroxyphenyl)Ethanol
55674-67-4		Boc-D-Thr-OH
931-40-8		4-Hydroxymethyl-1,3-dioxolan-2-one
306-08-1		Homovanillic Acid
2444-46-4		Nonivamide
188817-13-2		1H-Pyrazole,5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-
23981-80-8		2-(6-Methoxy-2-naphthyl)propionic acid
20300-59-8		7-Methoxycoumarin-3-carboxylic acid
35817-27-7		4-Ethoxycoumarin
475231-21-1		3'-Hydroxypterostilbene
831-61-8		Ethyl Gallate
120-51-4		Benzyl benzoate
4360-63-8		2-Bromomethyl-1,3-dioxolane
3400-55-3		2-Bromopropionaldehyde diethyl acetal
4870-65-9		alpha-bromophenylacetic acid
156682-53-0		3-Bromo-2-fluorophenol

References

1. Appel, Rolf. Angewandte Chemie International Edition in English, 1975, 14(12), 801-811.
2. Tönjes, Jan, et al. Organic Letters, 2023, 25(51), 9114-9118.
3. Roethle, Paul A., et al. Organic Letters, 2006, 8(25), 5901-5904.
4. Lee, Robert J., et al. Chemical Communications, 2017, 53(47), 6327-6330.
5. Yang, Yong-Hua, et al. The Journal of Organic Chemistry, 2005, 70(21), 8645-8648.