Given the significantly more favored hydrate of formaldehyde in the presence of water under neutral conditions, can we say that this is the slow step in iminium formation? Would removing water/working anhydrously (and thereby favoring the aldehyde form of formaldehyde) improve the rate of reaction?
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The formation of iminium ions from formaldehyde and a secondary amine typically involves the initial reaction between formaldehyde and the amine to form a hemiaminal, followed by dehydration to yield the iminium ion. In the presence of water, the hemiaminal can readily undergo hydration to form the hydrate of formaldehyde. This hydrate form of formaldehyde is indeed more stable in neutral conditions compared to the aldehyde form.
If the hydration of formaldehyde to its hydrate form is the slow step in iminium formation, then removing water or working under anhydrous conditions could potentially improve the rate of the reaction. By removing water, you are shifting the equilibrium away from the hydrate form of formaldehyde and toward the aldehyde form. This would make the formation of the hemiaminal, and subsequently the iminium ion, more favorable.
However, it's essential to consider the specific mechanism and kinetics of the reaction. While removing water may favor the formation of the aldehyde form of formaldehyde, it doesn't guarantee that the reaction will proceed faster. Other factors such as steric hindrance, electronic effects, and the stability of intermediates also influence the reaction rate.
In summary, removing water or working under anhydrous conditions may indeed improve the rate of iminium formation if the hydration of formaldehyde is the rate-determining step. However, the overall reaction rate depends on various factors, and experimental testing would be necessary to determine the effectiveness of working anhydrously.
SOURCES: https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(Morsch_et_al.)/19%3A_Aldehydes_and_Ketones-_Nucleophilic_Addition_Reactions/19.05%3A_Nucleophilic_Addition_of_Water-_Hydration https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/10%3A_Nucleophilic_Carbonyl_Addition_Reactions/10.06%3A_Imines https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(OpenStax)/19%3A_Aldehydes_and_Ketones-_Nucleophilic_Addition_Reactions/19.0 https://byjus.com/chemistry/mannich-reaction-mechanism/ https://www.ebi.ac.uk/chebi/searchId.do?chebiId=73080
