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Homework Help: Organic Synthesis: Reduction of ketone to alcohol

  1. May 12, 2009 #1
    Hi. I was to plan and conduct the reduction of 4-t-butylcyclohexanone into 4-t-butylcyclohexanol using NaBH4 as reducing agent, MeOH as solvent, and NH4Cl.

    My question is about the use of NH4Cl. How does it act as a quenching agent? I've figured out that it acts as a quenching agent by removing Hydride ions (NH-). But i'm not too sure if this is true. Furthermore, i am wondering why water/dilute HCl is less effective? Im not too sure if i'm right, but is it because H2O is a weak electrophile & hence cannot effectively quench NH- nucleophiles? But then the same cannot be said about HCl, as the H3O+ generated is a relatively stronger electrophile & then should be an effective quenching agent right?. A little confused about that. I cant seem to find any info on the net about such reagents and their use for quenching :(

    Secondly, how should experimental conditions be changed if i choose to use LiAlH4?

    I understand that: 1. An inert atmosphere (Nitrogen) is needed. 2. Anhydrous conditions are necessary. 3. Oil/graphite bath & not water bath should be used. But should there be any other drastic change in procedure? (Currently i am using NaBH4 in a chilled water bath, which is gradually warmed to room temperature)

    Thanks for all your help.

    Manraj Singh
    Last edited: May 13, 2009
  2. jcsd
  3. Nov 22, 2011 #2
    Remember that NH4Cl can be thought of as a product of a weak base and a strong acid making it an acidic salt. It is a protic salt so the NaBH4 will react with it to release H2. In MeOH, it allows the MeOH to protonate slightly and provide H+ that can react with all of the H- on BH4(-) and replace to form trimethoxy borates and H2.

    Alternatively, there are modifications of the reducing power of the boron hydrides that are affected by what is adducted to the boron hydrides.... The adduct NH3-BH3 is parent to the corresponding known adducts of tertiary amines and borane used for selective reduction. Stoichiometric amounts of NH4Cl and NaBH4 in an inert solvent could form NaCl and the ammonia-borane if the insoluble characteristics of each starting salt were not a problem and the solvent was something aprotic.

    Occasionally, NaBH4 reductions of ketones will use a non-protic Lewis acid to complex the ketone and activate it in a tautomer that allows for selective reduction. In reducing 1,4 tBuCyclohexanone, the tButyl group will largely lock the chair form with the t-Bu in an equatorial position (guache interactions). The attacking H- reagent has a a prefered direction to enter and the diastereomer ratio is affected by this. The ratio can be affected by the Lewis acid complex as new steric interactions are placed into effect.

    All of these aside, it appears that what needs to be done is as follows...

    The reaction is to place the ketone in a MeOH solution and add slowly to a stirred suspension of MeOH and NaBH4, continue stirring so that all of the newly formed alcohol Borate adduct is formed and no starting ketone can be detected by TLC, then release the alcohol by shifting the MeOH to have small amount of protonation so that the remaining Hydrides are slowly removed. The NH4CL works well for this since it is largely insoluble, and the NH3-BH3 adducts are also less reactive, making the workup gentle. The workup is completed by stirring in open air and allowing for moisture to absorb into the MeOH mixture to slowly decompose to salts and release the desired alcohol.

    LiAlH is tricky because it can start a fire if solutions are allowed to get moist. While there is active material in the finished reaction, it is also tricky to workup, as the material releases heat during the reaction with moisture; since alcohols are sufficiently acidic to decompose it,it is prefered to destroy it with dry alcohols, slowly added with stirring. Since LIAlH also acts as a Lewis acid with the ketone it is used to achieve a different course during a reduction than NaBH4- therefore affects the product of the reduction. Reactions are run at low temperatures to maximize the the thermal barriers to chair -boat of the adduct, and allow for clean high diasteroselectivity in the reduction. The reaction has to be cooled for workup, and small amounts of alcohol (iC3OH would work) need to be added with rapid stirring (with a reflux condensor in place to prevent too rapid of boiling)... frothing is likely, so be patient in adding the alcohol, especially if the solid suspension becomes gummy. The next additions of alcohol, can have a small amount of water, and once the H2 evolution is over, water that is acidified, is added to ice and the mixture poured on it to dissolve the gelatinous aluminum hydroxides, and complete the workup. Generally, will need several solvent extractions to isolate product.

    Good luck!
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