Total Synthesis Strychnine - Step 5

Time for another rather simple and common chemical reaction, which is treatment of the nitrile group with lithium aluminum hydride (LiAlH4), a very strong reducing agent.  Under most circumstances, we will likely avoid this reagent, not because of its hazards, but rather due to its reactivity.  LiAlH4 reduces a myriad of different functional groups.  From the common ester, to nitro, azide, oxime, to the often difficult to reduce amides and, in this case, nitriles.  Notice that in the reaction below, that the only reactive group is the nitrile.  Typically there will be other groups one has to worry about, but when there are not, lithium aluminum hydride is a great reagent because of the high yields and speed of the reaction.  Below is the step we will focus on today.

General:
In general, these LiAlH4 is run in ethereal solvents.  These include tetrahydrofuran, THF, and diethyl ether.  THF is more commonly used because of supposed impurities in diethyl ether, despite the higher solubility of the salt in ether (weird for a salt to be soluble in ether, a non-polar solvent).  These solvents should be dried using an SDS (solvent dispensing system) or other methods (drying over anhydrous salts, or some other common methods are here).  This is because of the reactivity of the reagent.  This reagent is much more reactive than sodium borohydride, for two reasons.  One, the lithium ion is smaller than sodium, this ion is involved in coordination with the group to be reduced (in this reaction is is the nitrogen of the nitrile).  Second, the aluminum is less electronegative than boron, and so the electrons are held on looser, and thus the hydrides have more "hydride character" than in the borohydride.  A reagent that is often omitted from undergraduates is lithium borohydride, which I'm sure you can guess has properties in-between the two.  For this reaction, only lithium aluminum hydride is strong enough to reduce the nitrile, and since there are no other ketones, aldehydes, amides, etc., we will only get reduction at our nitrile.  Lastly, when you see hydride reagents such as those just mentioned, you should always think nucleophile.  These all behave similarly in that the hydride ion behaves as a nucleophile, attacking electrophilic centers.  In this reaction, the carbon of the nitrile is the electrophile as it is triple bonded to the nitrogen, highly polarizing the carbon.  The mechanism for this reaction (general scheme) is below.  It is interesting to note that in fact the hydride adds twice to the nitrile to isolate the amine.  During the reaction, the remainder of the aluminum complex acts as basically a giant proton (more specifically, a lewis acid).

The aqueous work up does not occur until after the reaction is complete.  Otherwise we would destroy all of our hydride and turn it to hydrogen gas and aluminum hydroxide immediately (in fact, LiAlH4 reacts very violently with water).

Workup:
There are many ways to work up a reaction after it has reacted with the hydride.  One of the most common is to do a basic hydrolysis.  This is essentially the aqueous work up in the mechanism above.  The base acts to slow the rate of hydrogen gas evolution (low H+ concentration) and also to help hydrolyze the aluminum to form aluminum hydroxide as the final byproduct.  The aluminum hydroxide is not very soluble in THF, nor is it in water.  Because of this what we will see is a lot of precipitate starting to form.  This makes the workup quite simple, and all we need to do is filter off the salts, and our product should be soluble in the THF, so we can then just collect the liquid after rinsing away any product that adsorbed to our salt with a little solvent.  Another method which Woodward uses in this synthesis, is to used a saturated aqueous solution of sodium sulfate.  Now what does this accomplish?  Well, sodium sulfate first of all is an aqueous solution, this is really the most important part.  Secondly, the sulfate is a flocculant.  A flocculant is a compound that aids in precipitating things from solution, in this case, we want to precipitate the aluminum hydroxide.  The sulfate helps in doing this, giving us a again, a precipitate, from which we can collect the liquid from.  After this, Woodward had added some chloroform, likely to solubilize all of the organics, but not the salts.  After this, he removed the solvent leaving a goop behind.  Trituration from ether (essentially just adding ether, stirring to dissolve impurity, then removing ether leaving solid behind) gave the desired product which were light yellow crystals.  He recrystallized from benzene to obtain a purer product for analysis.

Notice that woodward did not use the other type of workup that is possible for this reaction, and that is an acidic workup.  In workups such as these, usually aqueous ammonium chloride is added to the solution to gently (relatively) protonate the amine, as well as degrade the remaining aluminum hydride.  This was not done however, because we are reducing the nitrile to a primary amine.  The primary amine is a very basic group, and so we would be left with a charged group, making isolation more difficult as it will not be very soluble in organic solutions, and separation from the lithium salts can be difficult (after all, the protonated form of the amine is really just a salt itself once it is dried).

The last thing I would like to mention is that this reaction was not done under nitrogen.  But why?  The hydride is very reactive to moisture in the air!  Well, in reactions like these, usually 3-5 equivalents of hydride is added.  So any losses to water in the air is not going to greatly affect the reaction.  If you were carrying out this experiment though, should you keep it under nitrogen?  Well, probably.  The thing is you can't add the hydride too fast or you will create too much exotherm.  But how to you add a solid reagent to a flask without exposing it to the atmosphere?  Unless you cary this out in a glovebox (not a good idea), you can't really add the solid.  So, what is sometimes done, is that the ethereal hydride solution is placed into a flask, and the compound we want to reduce is slowly added, after dissolving in solvent, to our solution, via syring, or addition funnel capped with a drying tube (calcium chloride tube on top of the addition funnel).

Well, that's all for today.  Please leave a comment if you have any other questions or if you like my blog.  It will be good to have some feedback.  Thanks!