{"id":1698,"date":"2018-11-29T21:41:05","date_gmt":"2018-11-29T21:41:05","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/?post_type=chapter&p=1698"},"modified":"2026-06-25T01:44:09","modified_gmt":"2026-06-25T01:44:09","slug":"21-3-formation-of-hydrates-hemiacetals-acetals","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry2\/chapter\/21-3-formation-of-hydrates-hemiacetals-acetals\/","title":{"raw":"21.3. Formation of hydrates, hemiacetals, acetals","rendered":"21.3. Formation of hydrates, hemiacetals, acetals"},"content":{"raw":" \r\n\r\n
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Addition of water to aldehydes\/ketones to form hydrates<\/strong><\/h2>\r\nGeminal diols<\/a>, usually referred to as hydrates<\/em><\/strong> of aldehydes or ketones, have two hydroxy groups attached to the same carbon; the carbon has the same oxidation state as the corresponding C=O.\u00a0 Like most carbonyl equivalents, hydrates are usually unstable compared to the C=O, which is why they can only rarely be isolated as stable compounds.\u00a0 However, when electron withdrawing groups (such as -CF3<\/sub>, -CCl3<\/sub> or another C=O) are attached to the C=O, the hydrate is stable enough to be made and isolated.\u00a0 One such compound is chloral hydrate<\/a>, formerly used as a sedative and as a knockout drug called a \u201cMickey Finn<\/a>\u201d in old gangster movies!\r\n\r\n\"\"\r\n\r\nWater is a weak nucleophile, and therefore it will only add to a carbonyl (aldehyde or ketone) that has been activated by H+<\/sup> to form its conjugate acid.\u00a0 The mechanism is exactly as shown in section 21.1.\u00a0 Using acetone as an example, the oxygen is first protonated to give the activated ketone; water adds via nucleophilic addition, then H+<\/sup> is lost again via a second acid-base reaction.\u00a0 (A second water molecule has been used here as the base to remove the H+<\/sup>.)\r\n

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Addition of alcohols to form hemiacetals and acetals<\/h2>\r\n<\/div>\r\n<\/header>
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\r\n\r\nLike water, alcohols are weak nucleophiles, and so again they will only add to a protonated carbonyl.\u00a0 The initial addition of one alcohol leads to a hemiacetal<\/em><\/strong>, analogous to a hydrate. The hemiacetal is not normally a stable end product; typically the process continues by losing a molecule of water then adding a second alcohol molecule to give finally an acetal<\/em><\/strong>.\u00a0 The entire process is reversible, and requires removal of water (using Le Chatelier\u2019s principle<\/a>) to drive the reaction to completion and give the acetal product.\u00a0 Both hemiacetals and acetals (as typical carbonyl equivalents) will easily revert to the carbonyl compound in the presence of added water, using the same acid catalysis. This is a good example of the principle of microscopic reversibility<\/a>; the acid catalyst lowers the energy barrier for both the forward and backward reactions.\u00a0 The reaction is shown using acetone as an example ketone.\r\n\r\n<\/div>\r\n<\/section>\"\"\r\n\r\n
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\r\n\r\nSometimes acetals made from ketones are referred to as ketals<\/a><\/em>.\u00a0 Note that only aldehydes and ketones react with alcohols in this way; esters and other carboxylic acid derivatives will not give isolable addition products even if water is removed.\r\n\r\nIn the laboratory, there are a couple of ways we can remove water.\u00a0 One is to use a Dean-Stark trap<\/a>, that allows water to separate out from a boiling mixture and be removed.\u00a0 The other is to use molecular sieves<\/a> \u2013 a form of activated clay that traps water inside its structure.\r\n

Detailed mechanism for acetal formation<\/strong><\/h2>\r\nAs mentioned above, the formation of the hemiacetal is very similar to formation of a hydrate.\u00a0 Starting from acetone 1<\/strong>, H+<\/sup> is attached to form the conjugate acid 2<\/strong>, then ROH adds via nucleophilic addition to form 3<\/strong>, and finally H+<\/sup> is lost to give hemiacetal 4<\/strong>.\u00a0 This marks a useful mid-point in the mechanism.\r\n\r\n\"\"\r\n\r\nTo go from the hemiacetal to the acetal, we need first to remove the OH group.\u00a0 This is done by attaching H+<\/sup> to the oxygen of the OH, giving 5<\/strong>, which is very similar in structure to 3<\/strong>.\u00a0 This can then lose water (by nucleophile elimination) to give an alkylated ketone 6<\/strong>, analogous to structure 2<\/strong>.\u00a0 As we can see, to go from 4<\/strong> to 5<\/strong> to 6<\/strong> we have gone through two steps that match the reverse reaction from 4<\/strong> to 3<\/strong> to 2<\/strong>.\u00a0 At this point, the mechanism starts going \u201cforward\u201d again, with a nucleophilic addition to 6<\/strong> to give 7<\/strong>, which then loses H+<\/sup> via acid-base to give the final acetal 8<\/strong>.\u00a0 These two steps from 6<\/strong> to 7<\/strong> to 8<\/strong> exactly match the earlier sequence 2<\/strong> to 3<\/strong> to 4<\/strong> which formed the hemiacetal.\r\n\r\n<\/div>\r\n

Acetals as protecting groups<\/strong><\/h2>\r\nAlthough acetals are unstable in the presence of aqueous acid, they are completely stable to most bases and nucleophiles.\u00a0 This makes them useful as protecting groups (see section 15.2.) for aldehydes and ketones for reactions involving strong nucleophiles such as RMgX or LiAlH4<\/sub> which react with C=O but not with an acetal.\u00a0 After reaction (elsewhere) with the strong nucleophile, the protecting group can easily be removed with aqueous acid (H3<\/sub>O+<\/sup>) to regenerate the original C=O.\u00a0 In the example shown, a Grignard reagent is made to selectively attack an ester group in the presence of a protected C=O; the workup of the Grignard reaction also serves to regenerate the ketone.\r\n\r\n\"A\r\n
\r\n\r\nCyclic acetals and hemiacetals in nature and in synthesis<\/strong>\r\n\r\nAlthough simple acetals and hemiacetals are unstable in the presence of aqueous acid, they are greatly stabilized when their formation gives a new ring.\u00a0 Where you have an alcohol and a carbonyl in the same chain, these will form a cyclic acetal or hemiacetal.\u00a0 This is often seen in nature in carbohydrates such as glucose.\u00a0 In the diagram below, the open chain form of glucose is shown with the OH and a C=O highlighted; this makes up less than 0.02% of the total glucose even in aqueous solution, and it easily cyclizes to give the more stable cyclic hemiacetal. If another alcohol group (such as fructose) replaces the hemiacetal OH in glucose this makes a full acetal, such as sucrose.\r\n\r\n\"Examples\r\n\r\nMore stable acetals can also be made from aldehydes and ketones by using a diol such as ethane-1,2-diol (ethylene glycol, HOCH2<\/sub>CH2<\/sub>OH) and propane-1,3-diol (HOCH2<\/sub>CH2<\/sub>CH2<\/sub>OH).\u00a0 Such acetals are often used as protecting groups in synthesis.\r\n

References<\/h3>\r\n<\/div>\r\n
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  1. Vollhardt, K. Peter C., and Neil E. Schore.\u00a0Organic Chemistry: Structure and Function. New York: W.H. Freeman and Company, 2007<\/li>\r\n \t
  2. Carey, Francis. Advanced Organic Chemistry. 5th ed. Springer, 2007.<\/li>\r\n<\/ol>\r\n<\/div>\r\n
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    Outside Links<\/h2>\r\n