Keith Usherwood Ingold Organic Chemistry

World leader in the chemistry of organic free radicals and first to recognize Vitamin E as a powerful agent that targets free radicals and neutralizes their harmful effects.

"If you took vitamin E this morning, you should know about this guy."

The Story

Broad Peak, Baffin Island

A rock clattered down, barely missing Keith Ingold’s head. It was the summer of 1973 in Northern Canada’s fantastic Baffin Island mountains. Ingold and his teammates were making a very dangerous descent down Belvedere Ridge or ‘Broad Peak’ as it was known. Thawing ice was releasing plenty of head-sized boulders.  It had been a warm day, so warm that after descending, they nearly went for a swim, even though a glacier was calving into the sea only 200 meters away. Fortunately, common sense prevailed.  They were members of the Ottawa Section of the Canadian Alpine Club on an expedition to an area of mountains that had never before been climbed.  

To get to this remote bit of Canada required three aircraft, the last of which involved a one-hour trip from Clyde River on a Twin Otter. The plane first flew over and surveyed a never before used ‘landing strip’, a rock strewn sand bar, and then carefully touched down so the first group could clear away the rocks before the plane took off to pick up other members of the party. To reach the mountain from the main camp the team required a Zephyr inflatable boat to cross Sam Ford fiord.  Numerous first ascents up mountains on both sides of this fiord were made on that trip.  Sam Ford Fjord

Five years later, Ingold went on a second expedition, this time to Bowman Island to climb a striking 570 meter high rock tower in the middle of a large fiord on the east coast of Ellesmere Island, roughly 1,300 km from the North Pole. He was disappointed when after reaching the summit he found a cairn indicating that a helicopter had landed there ahead of him and his team.  He enjoyed the challenge of being the first.

Keith Ingold was a chemist at the National Research Council in Ottawa specializing in free-radical chemistry, the study of short-lived highly reactive molecules.  After nearly two decades working purely on their physical aspects, in 1980 Ingold decided to focus on free-radical behaviour in biological systems and in particular the study of vitamin E. The scientific community’s views were split into two camps -- one believed that Vitamin E was not a radical-trapping antioxidant; the other felt that Vitamin E really was an antioxidant but only a very poor one.  However, both groups were in full agreement that Vitamin E did not owe its biological activity solely to its antioxidant activity. When Ingold looked up the structure of Vitamin E he found it was a mixture of four phenols (a type of aromatic alcohol on a six-carbon ring) and he knew all phenols were antioxidants.  He knew then and there, without any experiments, that Vitamin E was an antioxidant, and that all who  claimed otherwise must be wrong. Then the hard work began, proving experimentally that vitamin E was an antioxidant in living things, and exactly how it worked in so-called phospholipid bilayers (universal components of all cell membranes). 

Ingold began his bio-autoxidation and inhibition studies because he believed both Vitamin E camps were wrong. Both sides insisted on doing “biologically relevant” experiments to test for antioxidant activity.  This meant taking some animal tissue such as a rat’s liver, homogenizing it in a blender, then adding the compound being tested, incubating it at 37 degrees C for a period of time and then testing for the presence and quantity of a common fat oxidation product called MDA (malondialdehyde). The lower the MDA, the better the antioxidant was considered to be. Ingold believed such experiments were completely pointless and very far removed from biological  relevance because, as he used to say: “No animal is homogeneous."
 
In the traditional bioassay for vitamin E, a dozen or so E-deficient rats are dosed with the vitamin preparation, “sacrificed” after 24 hours, and the extent to which the E-deficiency had been reversed is measured. This may have provided statistically significant and hence uncritically accepted answers but, in Ingold’s view, several of these “answers” were unbelievable.  As just one example, the phenol, vitamin E, was claimed to have only half the vitamin E activity of the (chemically modified) vitamin E-acetate. "Surely Nature would never do that!" thought Ingold.  So he decided to experiment on himself.
 
He synthesized some vitamin E with 3 and with 6 deuterium atoms replacing an equivalent number of hydrogen atoms in the natural vitamin. Deuterium has twice the mass of hydrogen so this permitted the two deuterated vitamin E’s to be distinguished from each other and from “natural” vitamin E. One of the deuterated E’s was converted to the acetate.
 
Then one evening at supper Ingold took equal quantities of the deuterated E and differently deuterated E-acetate, washing it down with a large glass of wine. Ingold did not tell his wife what he was doing because these deuterated vitamin E’s might have proved fatal. Fortune prevailed and the next morning a blood test showed that equal concentrations of the two deuterated vitamin E’s were present, which demonstrated that the phenol and acetate versions were equally good sources of vitamin E. This prompted Ingold to claim he had scientific proof that “Men are not rats” to which his secretary immediately responded “All men are rats.”  Further experiments showed that her objections were valid. When rats were given the two deuterated vitamin E’s together in food (no wine) both forms also were taken up equally.  According to Ingold, "A triumph for the ladies, for science, and for common sense”. The acetate was twice as effective as the phenol only under the completely unrealistic  traditional bioassay lab procedures. 

As A Young Scientist...

Both of Dr. Ingold’s parents were physical organic chemists, so Keith was destined to become one as well. His mother, Edith Hilda Usherwood, had her own established research field when she married his father, later known as Sir Christopher Kelk Ingold, whose research was in a similar area.  They continued to collaborate, relying on extra help for raising their children.  But World War II intervened, and like many University College London (UCL) faculty, the Ingolds were evacuated to Aberystwyth in Wales, eventually joined by Keith and his two sisters.  In all, Keith attended about six schools during the war.

There was not much to do in Aberystwyth when Ingold first arrived there, so to keep him occupied, his father arranged for the departmental glass blower to teach Keith some of his skills on Saturdays.  One rainy Sunday, his father took Keith to the lab and decided to show him some interesting chemistry with sodium metal. Unable to find any sodium, his father cut several grams of potassium and threw it into a sink prefilled with water.  The results were spectacular.  There was an enormous bang, the sink was immediately emptied of water, and small puddles appeared on the floor by the hundreds, each one with bits of purple-flaming potassium speeding around the surface.  Keith was hooked.  He ended up helping his father clean up the lab, and a few years later entered UCL as a chemistry student where his father was Head of the Department.  It was also in Wales that Ingold first became interested in mountain climbing, tackling the Welsh peaks with one of his father’s PhD students.
 
Upon obtaining his PhD in Chemistry from Oxford University at the age of 22, Ingold emigrated to Canada to take a position as a Postdoctoral Fellow at the National Research Council laboratories in Ottawa where he remained for his entire career.  Later on he listed this as one of his wisest decisions.

The Science

"Keith Ingold is the undisputed world leader in the chemistry of organic free radicals and a true giant of Canadian science," said Dr. Thomas A. Brzustowski, President of the Natural Sciences and Engineering Research Council of Canada, when he presented Ingold with the Gerhard Herzberg Canada Gold Medal for Science and Engineering in 1998. "If you took a vitamin E supplement this morning, you should definitely know about him. He revolutionized the way we look at vitamins, being the first to recognize Vitamin E as a powerful agent that targets free radicals and neutralizes their harmful effects."

Free-radical chemistry is the study of the behaviour of highly reactive chemical species as they undergo very fast chain reactions. Ingold’s research involved many different and complicated molecules, but the basic mechanisms can be understood in simpler terms as shown in the accompanying graphic.

Chain reactions between Cl2  (chlorine gas) and CH4 (methane gas) molecules. (From: Master Organic Chemistry)

Free-Radical Chain Reactions

1. Initiation Phase: All free-radical reactions start with an Initiation Phase (figure), that uses heat, which causes molecular collisions, or photons from a powerful light source to break a bond in a molecule, thus creating highly reactive structures that desperately want to find a complementary structure for chemical bonding.  A container of only  Cl2,   for example, would create either Cl  atoms,  excited states of Cl2,  or, depending on the energy absorbed,  even excited states of Cl.  A possible reaction could be the recombination of two Cl atoms to form the Cl2 molecule.  Free-radical chemistry ignores these and is concerned with what happens when other molecules may be involved. Then the options greatly increase. It so happens that the structure of a Cl atom has an “electron hole” that wants to  bond with just the right structure to  “fill the hole”.
 
2. Propagation #1: CH4 (Methane) is added to the mixture:  one H-C  bond is broken and  a Cl-H bond is  created forming the ClH molecule (hydrochloric acid), leaving a free .CH3 radical. The Cl-H bond is stronger than the H-C bond, so the energy of the whole system has been lowered and energy is released. 
 
3. Propagation #2: The .CH3 radical may now combine with Cl2 to create a Cl-CH3 (Chloromethane) molecule and one lone Cl atom that is also a free-radical.  Thus the number of free-radicals is preserved.  As long as constituents are available, these two propagation cycles may repeat. 
 
4. Termination: When two free-radicals combine (Cl. + .CH3) thereby reducing the number of free-radicals in the container, the process terminates after free-radicals are eliminated.  
The rates at which different reactions occur in the illustrated system depend on a variety of factors such as the density of the constituents, the energy needed for breaking a bond,  and the energy gained in creating a bond.
 

Antioxidants

Antioxidants are chemicals that trap and neutralize free radicals, thus preventing their harmful effects. Oxidation is a complex series of chain reactions, and antioxidants play a special role in stopping the process. One example of oxidation is the way that an oil lubricant degrades over time while in normal service. The chemical and physical properties of the oil and its additives are impaired. Understanding why a lubricant oxidizes is essential to prevent, delay and monitor the process. 
 
Ingold’s early work was focused on determining the reaction rates for many constituents of free-radical propagations. His work consisted of quantifying free-radical reactions, which helped in the process of “designing” reactions for specific effects.  His early work (1955 to 1968) elucidated the kinetics and mechanisms of the oxidation of organic compounds. He explored the way antioxidants could slow such oxidative degradation.  This was a topic of fundamental importance since this chemistry is involved in the oxidative deterioration of engine lubricating oils, the perishing of rubber, the development of rancidity in food, and in the commercial production of numerous materials for the synthetic textile industry.  Although the mechanism of such autoxidation was understood in general terms, the specific chemistry by which most antioxidants operated remained a mystery until Ingold studied them.  Ingold was one of the first scientists in the world to apply a quantitative approach to the study of free radical chemistry—a major contribution to basic and applied chemistry. His early work contributed substantially to a number of areas of industrial importance in Canada and the United States. In the late 1960’s, Ingold provided the foundation for chemists to use free radicals in the synthesis of new, complex molecules. He also demonstrated that such reactions could be used to “clock”  the rates of other chemical reactions.
 
The culmination of Ingold’s earlier efforts involved the application of his quantitative approach to free-radical reactions important in the biological world.  Beginning in 1980 Ingold decided to clear up the confusion about the biological role of Vitamin E. His careful experiments proved that Vitamin E was a potent antioxidant that trapped highly reactive free-radicals before they could damage biological materials like proteins and lipids.  Ingold’s work proved that Vitamin E was the most important fat-soluble antioxidant in human blood, tissues and organs, as well as in cancer cells.  He used water-soluble versions of vitamin E to ameliorate the harmful effects of ischemia-reperfusion in dog hearts (a model for successful angioplasty following a heart attack) and to study the beneficial effects of Vitamin E pre-treatment of patients awaiting elective heart surgery.  
 
His work also led to greatly improved understanding of certain Vitamin E deficiency diseases. In the 1980’s, Ingold’s research led to the surprising discovery that Vitamin E in low density lipoproteins (LDL, “bad cholesterol”) could act as a pro-oxidant rather than an antioxidant. 
 
Ingold also worked on the chemistry of reactive oxygen species (ROS) and reactive nitrogen species (RNS) present in the human body. He invented the first trap for an RNS, allowing for elusive but important biochemical messenger radicals to be seen by spectroscopy in cell cultures and, potentially, in whole animals. Ingold’s greatest achievement was to make these fast, complex reactions almost totally understandable. He was the first to define the stability and persistence of free radicals and is a leader in defining their structure. 
 

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The Person

Birthdate
May 31, 1929
Birthplace
Leeds, England
Residence
Ottawa, Ontario
Family Members
  • Spouse: Carmen Cairine Hodgkin
  • Father: Sir Christopher Kelk Ingold
  • Mother: Edith Hilda Usherwood
  • Children: two sons and a daughter
Personality
Outgoing, adventurous
Other Interests
Mountaineering, skiing, water skiing, hang-gliding
Title
Distinguished Research Scientist
Office
Steacie Institute for Molecular Science
Status
Retired
Degrees
  • BSc University of London, 1949
  • PhD Oxford University 1951
Awards
  • American Chemistry Society, Petroleum Chemistry Award (1968)
  • American Chemistry Society, Linus Pauling Award (1988)
  • Royal Society of London, Davy Medal (1990)
  • American Chemistry Society, Arthur C. Cope Scholar Award (1992)
  • American Chemistry Society, James Flack Norris Award (1993)
  • Officer of the Order of Canada (1995)
  • Gerhard Herzberg Gold Medal for Science and Engineering, NSERC (1998)
  • Royal Society (London) Royal Medal (2000)
  • Order of Canada, Golden Jubilee Medal (2002)
  • Professional Institute of the Public Service of Canada, Gold Medal (2009)
  • Order of Canada, Diamond Jubilee Medal (2013)
  • Royal Society (London), Sir Derek Barton Gold Medal (2016)
Last Updated
January 16, 2017
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