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Role of 10-camphor sulfonic acid as a catalyst in protecting group chemistry
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Marsha Cayabyab
Role of 10-camphor sulfonic acid as a catalyst in protecting group chemistry
For a given protecting group, there is no single best way of introducing it, just as there is no single best way of oxidising an alcohol – the conditions you use depends upon the substrate you have and the tolerance of it towards things such as acid, base, and heat.
In your question you ask specifically about conditions to introduce a benzylidine acetal, namely why aqueous acids aren't used – the tl;dr answer is that they are!
Below is an excerpt from the section in Greene's Protecting Groups in Organic Synthesis that deals with formation of such a group:
PhCHO, ZnCl2, 28°C, 4 h.
PhCHO, DMSO, concd. H2SO4, 25°C, 4 h.
PhCHO, TsOH, reflux, H2O, 72% yield.
Sulfuric acid on silica gel, PhCH(OMe)2, 75–93% yield.
PhCH(OCH3)2, I2, CH3CN, 60–89% yield.
Taken from: Greene's Protecting Groups in Organic Synthesis
What all of these conditions have in common is that some kind of acid catalyst is required. Mineral acids (sulfuric), Lewis acids (zinc chloride or iodine) and organic acids (tosic acid) have all been shown to work in the literature, and indeed most people involved in complex molecule synthesis will have tried most of them.
Which condition is most appropriate is a matter of context (and often a lot of screening). Solid organic acids (tosic acid, camphor sulfonic acid, pyridine para-toluene sufonate) are often used in late-stage synthesis as they're able to be dried, this allows the reactions to be conducted under (almost) anhydrous conditions. Use of sulfuric acid dictates that water (quite a lot of it) is present, which can knock off other delicate protecting groups/functionality in a molecule.
For a given protecting group, there is no single best way of introducing it, just as there is no single best way of oxidising an alcohol – the conditions you use depends upon the substrate you have and the tolerance of it towards things such as acid, base, and heat.
In your question you ask specifically about conditions to introduce a benzylidine acetal, namely why aqueous acids aren't used – the tl;dr answer is that they are!
Below is an excerpt from the section in Greene's Protecting Groups in Organic Synthesis that deals with formation of such a group:
PhCHO, ZnCl2, 28°C, 4 h.
PhCHO, DMSO, concd. H2SO4, 25°C, 4 h.
PhCHO, TsOH, reflux, H2O, 72% yield.
Sulfuric acid on silica gel, PhCH(OMe)2, 75–93% yield.
PhCH(OCH3)2, I2, CH3CN, 60–89% yield.
Taken from: Greene's Protecting Groups in Organic Synthesis
What all of these conditions have in common is that some kind of acid catalyst is required. Mineral acids (sulfuric), Lewis acids (zinc chloride or iodine) and organic acids (tosic acid) have all been shown to work in the literature, and indeed most people involved in complex molecule synthesis will have tried most of them.
Which condition is most appropriate is a matter of context (and often a lot of screening). Solid organic acids (tosic acid, camphor sulfonic acid, pyridine para-toluene sufonate) are often used in late-stage synthesis as they're able to be dried, this allows the reactions to be conducted under (almost) anhydrous conditions. Use of sulfuric acid dictates that water (quite a lot of it) is present, which can knock off other delicate protecting groups/functionality in a molecule.
For a given protecting group, there is no single best way of introducing it, just as there is no single best way of oxidising an alcohol – the conditions you use depends upon the substrate you have and the tolerance of it towards things such as acid, base, and heat.
In your question you ask specifically about conditions to introduce a benzylidine acetal, namely why aqueous acids aren't used – the tl;dr answer is that they are!
Below is an excerpt from the section in Greene's Protecting Groups in Organic Synthesis that deals with formation of such a group:
What all of these conditions have in common is that some kind of acid catalyst is required. Mineral acids (sulfuric), Lewis acids (zinc chloride or iodine) and organic acids (tosic acid) have all been shown to work in the literature, and indeed most people involved in complex molecule synthesis will have tried most of them.
Which condition is most appropriate is a matter of context (and often a lot of screening). Solid organic acids (tosic acid, camphor sulfonic acid, pyridine para-toluene sufonate) are often used in late-stage synthesis as they're able to be dried, this allows the reactions to be conducted under (almost) anhydrous conditions. Use of sulfuric acid dictates that water (quite a lot of it) is present, which can knock off other delicate protecting groups/functionality in a molecule.
For a given protecting group, there is no single best way of introducing it, just as there is no single best way of oxidising an alcohol – the conditions you use depends upon the substrate you have and the tolerance of it towards things such as acid, base, and heat.
In your question you ask specifically about conditions to introduce a benzylidine acetal, namely why aqueous acids aren't used – the tl;dr answer is that they are!
Below is an excerpt from the section in Greene's Protecting Groups in Organic Synthesis that deals with formation of such a group:
What all of these conditions have in common is that some kind of acid catalyst is required. Mineral acids (sulfuric), Lewis acids (zinc chloride or iodine) and organic acids (tosic acid) have all been shown to work in the literature, and indeed most people involved in complex molecule synthesis will have tried most of them.
Which condition is most appropriate is a matter of context (and often a lot of screening). Solid organic acids (tosic acid, camphor sulfonic acid, pyridine para-toluene sufonate) are often used in late-stage synthesis as they're able to be dried, this allows the reactions to be conducted under (almost) anhydrous conditions. Use of sulfuric acid dictates that water (quite a lot of it) is present, which can knock off other delicate protecting groups/functionality in a molecule.
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