Morris S. Kharasch
Encyclopedia
Morris Selig Kharasch was a pioneering organic chemist
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 best known for his work with free radical
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...

 additions and polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...

s. He defined the peroxide effect, explaining how an anti-Markovnikov
Markovnikov's rule
In organic chemistry, Markovnikov's rule or Markownikoff's rule is an observation based on Zaitsev's rule. It was formulated by the Russian chemist Vladimir Vasilevich Markovnikov in 1870....

 orientation could be achieved via free radical addition. Kharasch was born in Russian Empire
Russian Empire
The Russian Empire was a state that existed from 1721 until the Russian Revolution of 1917. It was the successor to the Tsardom of Russia and the predecessor of the Soviet Union...

 in 1895 and immigrated
Immigration
Immigration is the act of foreigners passing or coming into a country for the purpose of permanent residence...

 to the United States at the age of 13. In 1919, he completed his Ph.D.
Doctor of Philosophy
Doctor of Philosophy, abbreviated as Ph.D., PhD, D.Phil., or DPhil , in English-speaking countries, is a postgraduate academic degree awarded by universities...

 in chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

 at the University of Chicago
University of Chicago
The University of Chicago is a private research university in Chicago, Illinois, USA. It was founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller and incorporated in 1890...

 and spent most of his professional career there. Most of his research in the 1920’s focused on organo-mercuric derivatives. He synthesized an important anti-microbial alkyl mercuric sulfur compound, thimerosal, commercially known as Merthiolate, which he patented in 1928 and assigned to the pharmaceutical
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

 company Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

. Merthiolate was introduced as a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 preservative in 1931, and by the late 1980’s thimerosal was used in all whole-cell DPT vaccine
DPT vaccine
DPT refers to a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis and tetanus...

s. Nobel laureate Herbert C. Brown
Herbert C. Brown
Herbert Charles Brown was a chemist and Nobel Prize in Chemistry laureate for his work with organoboranes....

 was one of his students during the 1930s. When World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

 began, the US government
Federal government of the United States
The federal government of the United States is the national government of the constitutional republic of fifty states that is the United States of America. The federal government comprises three distinct branches of government: a legislative, an executive and a judiciary. These branches and...

 recognized the need for a synthetic rubber
Synthetic rubber
Synthetic rubber is is any type of artificial elastomer, invariably a polymer. An elastomer is a material with the mechanical property that it can undergo much more elastic deformation under stress than most materials and still return to its previous size without permanent deformation...

 and employed the best chemists around the nation to aid in this effort. In 1942 Kharasch joined the American Synthetic Rubber Research Program and applied his knowledge of radical reactions to aid in the polymerization of synthetic styrene. In his later years, Kharasch devoted his attention to studying the Grignard reaction
Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon–carbon bonds...

 and in 1954 co-authored a book with O. Reinmuth entitled Grignard Reactions of Nonmetallic Substances.

Timeline of Kharasch's Life and Work>
1895 Born in Ukraine
1908 Moves to Chicago
1919 Obtains PhD from the University of Chicago
1928 Patents Merthiolate (thimerosal)
1931 Thimerosal is first used in vaccines
1933 Publishes "The Peroxide Effect in the Addition of Reagents to Unsaturated Compounds
1936 Founds the Journal of Organic Chemistry
1942 Works on the government sponsored wartime project “The American Synthetic Rubber Research Program”
1949 Receives the Scott Award from the Franklin Institute
1952 Receives the Richards Medal from the American Chemical Society
1957 death

Proposal for anti-Markovnikov addition: The peroxide effect

In 1869, a Russian
Russians
The Russian people are an East Slavic ethnic group native to Russia, speaking the Russian language and primarily living in Russia and neighboring countries....

 chemist named Vladimir Markovnikov demonstrated that the addition of HBr to alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

s always resulted in a specific orientation. Markovnikov's rule
Markovnikov's rule
In organic chemistry, Markovnikov's rule or Markownikoff's rule is an observation based on Zaitsev's rule. It was formulated by the Russian chemist Vladimir Vasilevich Markovnikov in 1870....

, which stems from these observations, states that in the addition of HBr or another hydrogen halide
Halide
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...

 to an alkene, the acidic proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....

 will add to the less substituted carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 of the double bond
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....

. This directed addition of a proton results in the more thermodynamically
Thermodynamics
Thermodynamics is a physical science that studies the effects on material bodies, and on radiation in regions of space, of transfer of heat and of work done on or by the bodies or radiation...

 stable carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...

 intermediate, as determined by degrees of substitution; more highly substituted carbocations are stabilized by the electron-pushing inductive effect of the surrounding carbon molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

s.

In his seminal 1933 paper entitled "The Addition of Hydrogen Bromide to Allyl Bromide", Kharasch proposed that the anti-Markovnikov addition of HBr to allyl bromide to yield 1,3-dibromopropane was due to the presence of peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

s. He termed this the “peroxide effect”, which he proposed proceeds through a free radical chain reaction
Chain reaction
A chain reaction is a sequence of reactions where a reactive product or by-product causes additional reactions to take place. In a chain reaction, positive feedback leads to a self-amplifying chain of events....

 addition. Elsewhere in the literature
Scientific literature
Scientific literature comprises scientific publications that report original empirical and theoretical work in the natural and social sciences, and within a scientific field is often abbreviated as the literature. Academic publishing is the process of placing the results of one's research into the...

, other examples of anti-Markovnikov additions were observed by Whitmore and Homeyer as well as Sherril, Mayer and Walter, all of whom rejected Kharasch’s conclusions. They instead argued that the direction in which the reaction proceeds is determined not by the presence or absence of peroxides, but by the nature of the solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

 in which the reaction is taking place. In this paper, Kharasch analyzed one at a time the effects of temperature, solvent, and light on the direction in which the reaction proceeded. He concluded that the presence of peroxides was the driving force for anti-Markovnikov addition and that any changes in temperature
Temperature
Temperature is a physical property of matter that quantitatively expresses the common notions of hot and cold. Objects of low temperature are cold, while various degrees of higher temperatures are referred to as warm or hot...

, solvent, or light
Light
Light or visible light is electromagnetic radiation that is visible to the human eye, and is responsible for the sense of sight. Visible light has wavelength in a range from about 380 nanometres to about 740 nm, with a frequency range of about 405 THz to 790 THz...

 affected the orientation of addition only through the chemistry of the peroxides.

Once Kharasch began determining the dibromopropane
Dibromopropane
Dibromopropane is a molecule that contains three carbon atoms, six hydrogen atoms, and two bromine atoms. It refers to any of four isomers:*1,2-Dibromopropane*1,3-Dibromopropane*1,1-Dibromopropane*2,2-Dibromopropane...

 compositions of the products under various conditions, he made a startling discovery. When allyl bromide reacted with HBr in vacuo (in the absence of air
Earth's atmosphere
The atmosphere of Earth is a layer of gases surrounding the planet Earth that is retained by Earth's gravity. The atmosphere protects life on Earth by absorbing ultraviolet solar radiation, warming the surface through heat retention , and reducing temperature extremes between day and night...

 or other oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 source), the average reaction time took about 10 days with an approximate yield
Yield (chemistry)
In chemistry, yield, also referred to as chemical yield and reaction yield, is the amount of product obtained in a chemical reaction. The absolute yield can be given as the weight in grams or in moles...

 of 88%, the majority of which was the expected (according to Markovnikov's rule
Markovnikov's rule
In organic chemistry, Markovnikov's rule or Markownikoff's rule is an observation based on Zaitsev's rule. It was formulated by the Russian chemist Vladimir Vasilevich Markovnikov in 1870....

) 1,2-dibromopropane (65-85%). In contrast, when the reaction was run in the presence of air or oxygen, it lasted a markedly shorter time (with great variation), in one case only taking one hour to reach completion. More importantly, however, is that the major product of these additions was the 1,3-dibromopropane, constituting approximately 87% of the product. Since the only apparent variable that had changed was the presence of oxygen (other gases found in air were tested individually and did not show the same effect), Kharasch hypothesized
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...

 that the rapid anti-Markovnikov addition of HBr to allyl bromide was the result of trace amounts of peroxide in the reaction mixture that could have resulted from the interaction of molecular oxygen in its diradical triplet state and allyl bromide to form allyl bromide peroxide . From there, the weak peroxide O-O bond (~51 kcal/mol)(3) could be cleaved by incident light, causing homolytic cleavage
Homolysis
In general it means breakdown to equal pieces There are separate meanings for the word in chemistry and biology.-Homolysis in chemistry:...

 and creating the peroxide radical. Even trace amounts of this allyl bromide peroxide radical would then be sufficient to begin a chain reaction whereby a hydrogen atom would be abstracted from the HBr, leaving a Br radical. This Br radical would then combine with an electron
Electron
The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...

 from the double bond of allyl bromide at the less-highly substituted carbon, giving the more stable 2o radical. Reaction of this radical with another HBr molecule would cause the abstraction of another H molecule and would complete the anti-Markovnikov addition. Since the Br radical is regenerated, the reaction would continue to proceed at a fairly quick pace until the reactants were exhausted and/or the radical species were terminated.

Establishment of the peroxide effect

The validity of Kharasch’s proposal rested on the existence of peroxide in the reaction mixture, of which he had no direct evidence
Evidence
Evidence in its broadest sense includes everything that is used to determine or demonstrate the truth of an assertion. Giving or procuring evidence is the process of using those things that are either presumed to be true, or were themselves proven via evidence, to demonstrate an assertion's truth...

. Because he had no means of isolating the proposed allyl
Allyl
An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene , attached to a vinyl group . The name is derived from the Latin word for garlic, Allium sativum. Theodor Wertheim isolated an allyl...

 bromide peroxide, he performed an adapted version of the thiocyanate
Thiocyanate
Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates...

 test, an analytical test
Analytical chemistry
Analytical chemistry is the study of the separation, identification, and quantification of the chemical components of natural and artificial materials. Qualitative analysis gives an indication of the identity of the chemical species in the sample and quantitative analysis determines the amount of...

 that is often employed to check shelf-stored reagent
Reagent
A reagent is a "substance or compound that is added to a system in order to bring about a chemical reaction, or added to see if a reaction occurs." Although the terms reactant and reagent are often used interchangeably, a reactant is less specifically a "substance that is consumed in the course of...

s for their peroxide content. In addition to the thiocyanate test, Kharasch further supported the idea of a peroxide-induced chain reaction
Chain reaction
A chain reaction is a sequence of reactions where a reactive product or by-product causes additional reactions to take place. In a chain reaction, positive feedback leads to a self-amplifying chain of events....

 by showing that the addition of antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

s to the reaction mixture caused the reaction to proceed in aerobic conditions much as it would have if it were in vacuo
Vacuum
In everyday usage, vacuum is a volume of space that is essentially empty of matter, such that its gaseous pressure is much less than atmospheric pressure. The word comes from the Latin term for "empty". A perfect vacuum would be one with no particles in it at all, which is impossible to achieve in...

, producing the slowly forming 1,2-dibromopropane. The job of an antioxidant is to act as a radical scavenger, either accepting or donating an electron to a radical species
Chemical species
Chemical species are atoms, molecules, molecular fragments, ions, etc., being subjected to a chemical process or to a measurement. Generally, a chemical species can be defined as an ensemble of chemically identical molecular entities that can explore the same set of molecular energy levels on a...

. The result is that the radical becomes effectively neutralized
Neutralization
In chemistry, neutralization, or neutralisation is a chemical reaction in which an acid and a base react to form a salt. Water is frequently, but not necessarily, produced as well. Neutralizations with Arrhenius acids and bases always produce water:Y and X represent a monovalent cation and anion...

, while the antioxidant itself becomes a radical. Antioxidants, however, are much less reactive radicals as they are usually rather large and resonance
Resonance
In physics, resonance is the tendency of a system to oscillate at a greater amplitude at some frequencies than at others. These are known as the system's resonant frequencies...

 stabilized aromatic
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 compounds, and therefore prevent undesired oxidations from occurring. The addition of antioxidants in the reaction mixture in this experiment would effectively quench
Quench
In materials science, quenching is the rapid cooling of a workpiece to obtain certain material properties. It prevents low-temperature processes, such as phase transformations, from occurring by only providing a narrow window of time in which the reaction is both thermodynamically favorable and...

 the peroxide radicals, and therefore the reaction would then proceed to form (mainly) the 1,2 –dibromopropane product, as was observed.

Effect of temperature on addition orientation

Because other experimenters had reported anti-Markovnikov products and had attributed them to other factors, Kharasch addressed several variables to see if they also had an effect on the orientation of HBr addition to allyl bromide. Although an increase in temperature at first glance seemed to direct the orientation of the addition to the anti-Markovnikov product, Kharasch explained that that this temperature effect must be viewed as secondary to the peroxide effect, exemplified by the fact that the addition of antioxidants at elevated temperatures can produce a high 1,2- dibromopropane yield.

Effect of solvent on addition orientation

Next Kharasch observed the effect of different solvents on the orientation of addition, which his opponents proposed was the cause of other observed anti-Markovnikov products. He chose solvents with a wide range of dielectric constants (i.e. polarities). In the presence of air, the solvents with a high dielectric constant
Dielectric constant
The relative permittivity of a material under given conditions reflects the extent to which it concentrates electrostatic lines of flux. In technical terms, it is the ratio of the amount of electrical energy stored in a material by an applied voltage, relative to that stored in a vacuum...

 tended to form the 1,2- product while the solvents with low dielectric constant tended to form the 1,3- product. However, these results could also be viewed in accord with the peroxide effect theory; many of the solvents with high dielectric constants were able to act as antioxidants themselves, therefore quenching any radical formation and promoting the 1,2- addition whereas the solvents of low dielectric constant often had little or no antioxidant ability and so the 1,3- addition proceeded uninhibited. Kharasch concluded that the solvent may contribute to the orientation of addition if it 1.) has an effect on the stability of the peroxide or its radical 2.) prevents the initial formation of the peroxide or 3.) differentially affects the rates of the competing addition reactions. Kharasch went on further to show that when both the temperature and the solvent were varied together, they still acted independently of one another, in the manners described above. Kharasch also showed that strong illumination at a variety of wavelengths favored the 1,3- addition, but in the presence of strong antioxidants the electrophilic addition
Electrophilic addition
In organic chemistry, an electrophilic addition reaction is an addition reaction where, in a chemical compound, a π bond is broken and two new σ bonds are formed...

 was favored, exhibiting that this variable too only exerts its effects through affecting the reactivity of the peroxide.

Future implications of his work

The research conducted by Kharasch prompted further studies of free radical reactions. From this continued research, industrial polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...

 reactions of unsaturated
Saturation (chemistry)
In chemistry, saturation has six different meanings, all based on reaching a maximum capacity...

 hydrocarbons were discovered and mass production
Mass production
Mass production is the production of large amounts of standardized products, including and especially on assembly lines...

 of synthetic rubber and plastic
Plastic
A plastic material is any of a wide range of synthetic or semi-synthetic organic solids used in the manufacture of industrial products. Plastics are typically polymers of high molecular mass, and may contain other substances to improve performance and/or reduce production costs...

s was possible. Through similar radical processes, standard alkanes are halogenated and made substantially more reactive. This allows them to be very useful intermediates in organic syntheses
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...

. While standard conditions generally support one orientation of addition, in some cases it may be advantageous to have the halide
Halide
A halide is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative than the halogen, to make a fluoride, chloride, bromide, iodide, or astatide compound. Many salts are halides...

 on the less highly substituted carbon, in the anti-Markovnikov position. In this case a free radical addition
Free radical addition
Free radical addition is an addition reaction in organic chemistry involving free radicals. The addition may occur between a radical and a non-radical, or between two radicals....

step may be the key to obtaining the desired ultimate product, and is possible because of the work of Morris Kharasch.

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. Accessed 2007-01-20
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