#49 from R&D Innovator Volume 2, Number 8          August 1993

A $2 Present, Research for War, and a Nobel Prize
by Herbert C. Brown, Ph.D.

Dr. Brown, a 1979 Nobel Prize winner in chemistry, is the R.B. Wetherill Research Professor of Chemistry at Purdue University.  Although he officially retired in 1978 (at 66), he continues to carry on research with approximately 16 postdoctorate co-workers.

The 500th anniversary of the discovery of America by Christopher Columbus was celebrated in 1992.  Obviously, no new physical continents remain to be discovered, but many new continents of science await discovery by enthusiastic explorers. 

Over the past 50 years, my students and I found and explored the Borane Continent, a feat that led to the awarding of the Nobel Prize.  Let me tell you how this continent of science was discovered and mapped.

Beginnings

My early education was erratic because my father died when I was 14 and I had to work to help support my mother and three sisters.   For two years after high school, I tried to find a reasonable job, but this was the Great Depression, so in 1932 I enrolled in a small junior college.  Having been told that the field paid well, I opted for electrical engineering.  I had to take chemistry in the first year, and since it fascinated me, I decided to ignore the money and became a chemistry major. 

In 1933 the college itself became a victim of the Depression.  When it went out of business, I had nowhere to go.  The following year, I enrolled in a junior college that had just been opened by the City of Chicago, and then won a scholarship that permitted me to receive a bachelor's degree in chemistry from the University of Chicago in 1936.

A Portending Gift

I decided to do doctoral research on the hydrides of boron.  At that time, it was a highly exotic field, and I had no idea it would lead to methods for cheaply and efficiently producing pharmaceuticals and other valuable compounds. 

My decision for a thesis field, I admit in retrospect, was made as much by economics as anything else.  Let me explain how one classmate influenced my decision.  When I received the B.S. degree, my girlfriend, Sarah Baylen, gave me a graduation present.  This book, Hydrides of Boron and Silicon, piqued my interest.

But why did Sarah select this book from the hundreds of chemistry books at the UC bookstore?  Not having much money, she picked the cheapest chemistry book in the store and paid $2.00 for it.  So here's one method for selecting a research field leading to a Nobel Prize! 

But let me explain more about boron.  Compounds of carbon, the central element of the periodic table, form the basis of life.  The simplest hydrogen-carbon compound, methane, has one carbon atom joined to four hydrogen atoms.

To the right of carbon is nitrogen; the simplest hydrogen-nitrogen compound is NH3, ammonia.  Move left from carbon and you find boron; the simplest hydrogen compound of boron is BH3, borane.  While methane and ammonia are found in nature and used by the billions of pounds each year as fuel and fertilizer, respectively, borane is not found in nature--it is too reactive.  The interest in borane was largely theoretical.  It could be isolated only as the dimer, diborane, and there was considerable speculation about the electronic structure involved in the dimerization.

When I began work, diborane could only be made in tiny quantities by very difficult methods.  I'd guess that not more than a dozen chemists throughout the world had ever made or done research with this rare material.

For my thesis, I undertook to explore the reaction of diborane with aldehydes and ketones.  I soon found that diborane would conveniently reduce these compounds, but there was absolutely no interest in my finding.  How could organic chemists use diborane as a reagent if it was so rare?

I'd like to say that we had the good sense to search for a practical synthesis of diborane, allowing organic chemists to use our process to reduce aldehydes and ketones.  But we didn't have enough good sense; what we had were the imperatives of war research. 

Armed with my Ph.D. and allied with Sarah, who was now my wife, I looked for an industrial job.  But I could not persuade anyone to hire me, and just when I thought I was facing catastrophe, I was offered a postdoctorate at the University of Chicago. 

Trouble Keeping Up with War Needs

The government wanted to find volatile, noncorrosive compounds of uranium, without the corrosive properties of uranium hexafluoride.  Although we were not informed of the objective, I know now that we were working for the atom bomb project.  We used diborane to synthesize uranium borohydride.  As it fit the criteria, we were asked to make a large quantity for testing.

By this time, World War II had begun, and it soon became apparent that, even with six people operating six diborane generators, we would not be able to supply sufficient diborane.  We had to find a more practical route.

Our first attempt, the reaction of lithium hydride with boron trifluoride, produced plenty of diborane.  When we happily reported our success to the government, they told us lithium hydride was urgently needed for the war; none could be spared for us.  Someone suggested that we use sodium hydride, but it would not react with boron trifluoride.

Then we discovered that methyl borate would react with sodium hydride to form a new compound, sodium trimethoxyborohydride, which would do everything lithium hydride would.  In particular, it would react with boron trifluoride to produce diborane.  And diborane reacted to produce sodium borohydride, a new compound of major importance.

Finally ready to synthesize quantities of uranium borohydride, we learned there was no further need for new noncorrosive, volatile uranium compounds, as the difficult handling of uranium hexafluoride had been mastered. 

This was 1943.  The Signal Corps told us about their problem in field-generating hydrogen.  They thought that our new chemical, sodium borohydride, might solve their problem.  Although we had never used it for hydrogen generation, we had no doubt it would react with water to liberate hydrogen.

When they asked for a demonstration, I placed the borohydride in a flask and put the entire assembly behind an explosion screen since I didn't know how violent the reaction might be.  Everyone watched from a safe distance while I cautiously reached behind the screen and turned the stopcock to drip water onto the borohydride.

The borohydride dissolved and the solution sat there looking at me!  No explosion--and no hydrogen.  This was one of the great shocks of my life and was the way we discovered that sodium borohydride possesses an unusual stability in water. 

At least we disproved our prediction that hydrogen would be produced.  However, we persuaded the Signal Corps to support research into improved preparations for sodium borohydride.  We discovered that at elevated temperature, sodium hydride and methyl borate would react to produce a mixture of sodium borohydride and sodium methoxide. 

We needed a solvent to separate the two products.  We tried using acetone to separate borohydride from other reaction products, but the acetone was converted to isopropyl alcohol--the borohydride added hydrogen atoms to the acetone.  Thus we discovered a major application of sodium borohydride—to hydrogenate organic molecules.  We went on to discover suitable solvents and suitable catalysts for the hydrolysis.

The Signal Corps was delighted with the project and proposed to have the material made on a large scale by the Ethyl Corporation.  But then a directive from Washington told us the end of the war was in sight and no new war plants would be built. 

After the war, Metal Hydrides Co. (now Morton, International) manufactured sodium borohydride; it is currently made by essentially our process in the millions of pounds per year.

Even More Surprises

In 1947, I joined the Purdue faculty and returned to studying borohydride chemistry.  Esters such as ethyl acetate and ethyl stearate took up two hydrogens from borohydride, as expected.  We found that ethyl oleate took up 2.37 hydrogens, a minor discrepancy we might have swept under the rug.  However we discovered that the hydrogens were going into the carbon-carbon double bond in ethyl oleate.  This reaction, hydroboration, turned out to be quite valuable since it provided a simple means for converting unsaturated organic compounds into other products.

We explored hydroboration systematically for 10 years, and friends asked me why.  It was a clean reaction, they pointed out, but all it did was produce organoboranes, on which little work had been performed since their discovery in 1862.  They therefore concluded that organoboranes could be of little interest.

We bided our time, then turned to the chemistry of organoboranes.  There, we discovered an unimaginable gold mine, a series of compounds that have done practically everything we have "asked" them to do and that have become the most versatile intermediates available to chemists.  We can now use them to convert olefins and other unsaturated organic molecules into almost any known class of organic compounds (alcohols, aldehydes, ketones, acids, amines, etc.).

Moreover, they exhibited a most unusual feature:  retention of stereochemistry.  Let me explain.  Unlike biologically produced compounds, chemically synthesized carbon compounds often exist as a mixture of stereoisomers--mirror images comparable to right and left hands.  This is a problem in the manufacture of pharmaceuticals because usually only one of a stereoisomer pair is active.  Boron chemistry, however, gives us a practical method for making only one of the pair, promising to revolutionize the economics of the pharmaceutical industry.

For example, Prozac, an antidepressant, introduced by Eli Lilly several years ago, is sold only as a mixture of the two stereoisomers.  Attempts to separate the mixture into the individual isomers failed.  But we found it easy to synthesize the individual stereoisomers by our borane route of "asymmetric synthesis."

New Continents of Science to Discover

In 1936, when I received my bachelor's degree, I considered organic chemistry a mature science, with essentially all important reactions and structures nailed down.  The major challenges seemed to consist of working out the reaction mechanisms and improving reaction yields.  I was wrong.

I know many researchers today feel as I did back then.  But I see no reason to believe that the next 56 years will be any less fruitful than the past 56.  We're still naming the new continents of science!