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Though the exact number given varies from 0.02% to 3%, it's well agreed that glucose spends a very small percentage of its time in aqueous solution as a linear aldehyde. Glucose's overwhelming preference as a cyclic pyranose is commonly explained by the cyclization being intramolecular; while the aldehyde group in its linear form can react with other molecules like protein and lipids during rare encounters, it far more readily reacts with an alcohol group that is always around by virtue of being on the same molecule.

My problem with that explanation is that there is indeed another molecule that is always around in aqueous solution: water. All sources I could find said that the common instability of hemiacetals and geminal diols are both explained by oxygen repulsion. Therefore, I would expect there to be a glucose-geminal diol concentration comparable to the cyclic hemiacetal concentration in aqueous solution, yet I cannot find any mention of a glucose-geminal diol, as if it didn't exist. What am I missing?

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Why doesn't water react with the aldehyde to form a linear geminal diol?

It does, and depending on the nature of the aldehyde, this will be the major species. You are right in saying that the high concentration of water helps to form the diol. In other solvents, the diol form will be present at lower fraction, even when they contain a bit of water. The Wikipedia article on geminal diols has some equilibrium constants for various aldehydes and ketones in aqueous solution: https://en.wikipedia.org/wiki/Geminal_diol#Reactions

Glucose's overwhelming preference as a cyclic pyranose is commonly explained by the cyclization being intramolecular; while the aldehyde group in its linear form can react with other molecules like protein and lipids during rare encounters, it far more readily reacts with an alcohol group that is always around by virtue of being on the same molecule.

Yes, that is the special thing about glucose: the aldehyde can form an intramolecular hemiacetal without strain. It can also form a geminal diol, but that is no different from other aldehydes, so it is usually not mentioned in that context.

Is the geminal diol ever important for the reactivity?

There is an enzyme called aryl sulfatase which has an aldehyde (a cysteine modified post-translationally to a formyl glycine) in its active site [review]. X-ray crystal structures show that the main form is the hydrated species, i.e. the geminal diol. In the suggested mechanism, one hydroxyl attacks a sulfate ester, displacing the alcohol. Then, the second hydryoxyl group reforms the aldehyde and releases the sulfate in an elimination reaction.

Are there other instances where we don't explicitly mention reaction with water?

The hydrogen ion occurs in aqueous solution in various hydrated states. Carbon dioxide in aqueous solution occurs either hydrated (carbonic acid) or not. In either case, it is easier to lump the species into one than to talk about them separately.

What is the equilibrium constant for the hydration of the aldehyde in glucose

I did not find data for glucose, but did find some for glyeraldehyde 3-phosphate (Petersson and Petersson 1999). [In the HTML version of the paper, some equations and schemes don't show, but the PDF is an improvement.] In aqueous solution, only about 3% of this phosphorylated sugar is present in the aldehyde form. In the reaction they were studying, only the aldehyde form reacts in the enzymatic reaction, so there is a slow non-enzymatic first step to dehydrate the diol and a fast second step.

Wikipedia has an article on glycoaldehyde, with 4% of it in the aldehyde form. If glucose behaves in a similar manner, most of the linear form would be in the diol form. Equilibrium constants given in the literature probably use the total concentration of linear glucose (hydrated or not) in the equilibrium constant expression rather than the actual concentration of aldehyde.

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  • $\begingroup$ I did read that geminal diol stability varies and why (oxygen repulsion). However, I read the exact same reasons for hemiacetal instability. So I figured I should find hard numbers like equilibrium constants. The only source I can find showing equilibrium constants for a wide variety of carbonyl species is a page of lecture notes that cites two old sources, one for hemiacetals and one for hydrates, and it suggests that the more readily an aldehyde reacts with water, the more readily it reacts with methanol. I can't find a single mention of a glucose-geminal-diol, like it didn't exist. $\endgroup$ – BatWannaBe Apr 15 at 18:32
  • $\begingroup$ You are referring to this source $\endgroup$ – Karsten Theis Apr 15 at 18:44
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    $\begingroup$ Yes, exactly. Not great because the methanol is the most similar to water in size and shape of all the alcohols, but it was the only source I could find with both hemiacetal and hydrate reactions for a wide variety of species that wasn't behind a paywall. $\endgroup$ – BatWannaBe Apr 15 at 18:55
  • $\begingroup$ @BatWannaBe I added two references (still not exactly what you were asking, but relevant). $\endgroup$ – Karsten Theis Apr 15 at 19:31

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