What Is Grob Fragmentation Reaction?
In a fragmentation reaction, a molecule breaks into three fragments. The electrophilic leaving group a-b reacts to form a more stable molecule with a positive or neutral charge. The intermediate group c-d reacts to form a molecule containing an unsaturated bond. The nucleophilic leaving group L leaves atom d with an electron pair.
This type of reaction was documented as early as the 18th century. In 1952, Eschenmoser recognized the universality of this type of reaction and provided a correct explanation. In the 1950s, Grob conducted a very detailed study and summary of this type of reaction, and thus this broad category of reactions became known as Grob reactions. Since then, this type of reaction has been widely used in organic synthesis, becoming an effective method for ring-opening and medium-sized ring synthesis.
Fig 1. Grob fragmentation reaction and its mechanism. [1,2]
- Reagents:
a) Strong base: Common choices include alkali metal alkoxides (e.g., KOt-Bu, NaOEt), metal amides (e.g., NaNH2, LDA), organolithiums (e.g., BuLi, with caution), or non-nucleophilic bases (e.g., DBU, DABCO).
b) Aprotic solvent: Typically required (e.g., THF, DME, DMSO, toluene) under anhydrous conditions. - Reactants:
The symbols in the Grob reaction equation can be carbon, oxygen, nitrogen, phosphorus, boron, silicon, halogens, and so on. Therefore, many molecules with electrophilic leaving groups, intermediate groups, and nucleophilic leaving groups are capable of undergoing effective Grob reactions. In 1967, Grob provided a detailed summary of the reactions discovered in his review. [3]
Fig 2. Groups that can undergo the Grob reaction.
- Products:
Alkenes; carbonyl compounds; expelled leaving group (X⁻).
Mechanism of Grob Fragmentation
Molecules capable of undergoing Grob reactions also have other reaction possibilities. Fig 3 shows a reaction carried out in an alcohol solvent. In addition to Grob reactions, molecules can also undergo elimination reactions, substitution reactions, cyclization reactions, and other reactions to ultimately produce different products. The distribution of products is determined by both electronic and steric effects.
Fig 3. Alternative reaction pathways for molecules undergoing the Grob reaction.
Although there are three possible mechanisms for the Grob reaction, the stepwise positive ionization mechanism and the stepwise negative ionization mechanism are less common and often occur simultaneously with other side reactions. The most common mechanism, shown in Fig 1, is a concerted mechanism. This mechanism requires that the X and D groups maintain a trans-coplanar configuration of their electron orbitals. However, in some molecules with strain, cis fragmentation reactions can also occur.
Example Applications of Grob Fragmentation
- Example 1: Cao, Liming et al. reported that Grob-type fragmentation releases paracyclophane ring strain in the late precursor of Haouamine A. [4]
- Example 2: Gu, Qi et al. used Grob fragmentation technology to synthesize clavulactone analogs. [5]
Fig 4. Synthetic examples via Grob fragmentation.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 235-237.
- Prantz, Kathrin, et al. Chemical reviews, 2010, 110(6), 3741-3766.
- Grob, C. A., et al. Angewandte Chemie International Edition in English, 1967, 6(1), 1-15.
- Cao, Liming, et al. Organic Letters, 2019, 21(5), 1538-1541.
- Gu, Qi, et al. Organic Letters, 2019, 21(13), 5082-5085.
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