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Morris Selig Kharasch (August 24, 1895 – October 9, 1957) was a pioneering
organic chemist Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
best known for his work with
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...
additions and
polymerization In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
s. He defined the peroxide effect, explaining how an anti-Markovnikov orientation could be achieved via free radical addition. Kharasch was born in the
Russian Empire The Russian Empire was an empire and the final period of the Russian monarchy from 1721 to 1917, ruling across large parts of Eurasia. It succeeded the Tsardom of Russia following the Treaty of Nystad, which ended the Great Northern War. ...
in 1895 and
immigrated Immigration is the international movement of people to a destination country of which they are not natives or where they do not possess citizenship in order to settle as permanent residents or naturalized citizens. Commuters, tourists, and ...
to the United States at the age of 13. In 1919, he completed his
Ph.D. A Doctor of Philosophy (PhD, Ph.D., or DPhil; Latin: or ') is the most common degree at the highest academic level awarded following a course of study. PhDs are awarded for programs across the whole breadth of academic fields. Because it is ...
in
chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds made of atoms, molecules and ions ...
at the
University of Chicago The University of Chicago (UChicago, Chicago, U of C, or UChi) is a private research university in Chicago, Illinois. Its main campus is located in Chicago's Hyde Park neighborhood. The University of Chicago is consistently ranked among the b ...
and spent most of his professional career there. Most of his research in the 1920s focused on organo-mercuric derivatives. He synthesized an important anti-microbial
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloalk ...
mercuric sulfur compound,
thimerosal Thiomersal (INN), or thimerosal (USAN, JAN), is an organomercury compound. It is a well-established antiseptic and antifungal agent. The pharmaceutical corporation Eli Lilly and Company gave thiomersal the trade name Merthiolate. It has been u ...
, commercially known as Merthiolate, which he patented in 1928 and assigned to the
pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
company
Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
. Merthiolate was introduced as a
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
preservative in 1931, and by the late 1980s thimerosal was used in all whole-cell
DPT vaccine The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus. The vaccine components include diphtheria and tetanus toxoids and either kille ...
s. Nobel laureate
Herbert C. Brown Herbert Charles Brown (May 22, 1912 – December 19, 2004) was an American chemist and recipient of the 1979 Nobel Prize in Chemistry for his work with organoboranes. Life and career Brown was born Herbert Brovarnik in London, to Ukrainian Jewis ...
was one of his students during the 1930s. When
World War II World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposin ...
began, the
US government The federal government of the United States (U.S. federal government or U.S. government) is the national government of the United States, a federal republic located primarily in North America, composed of 50 states, a city within a feder ...
recognized the need for a
synthetic rubber A synthetic rubber is an artificial elastomer. They are polymers synthesized from petroleum byproducts. About 32-million metric tons of rubbers are produced annually in the United States, and of that amount two thirds are synthetic. Synthetic rubbe ...
and employed the best chemists around 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 Styrene () is an organic compound with the chemical formula C6H5CH=CH2. This derivative of benzene is a colorless oily liquid, although aged samples can appear yellowish. The compound evaporates easily and has a sweet smell, although high concen ...
. In his later years, Kharasch devoted his attention to studying the
Grignard reaction The Grignard reaction () is an organometallic chemical reaction in which alkyl, allyl, vinyl, or aryl-magnesium halides ( Grignard reagent) is added to a carbonyl group in an aldehyde or ketone. This reaction is important for the formation of ...
and in 1954 co-authored a book with O. Reinmuth entitled ''Grignard Reactions of Nonmetallic Substances''.


Proposal for anti-Markovnikov addition: The peroxide effect

In 1869, a
Russian Russian(s) refers to anything related to Russia, including: *Russians (, ''russkiye''), an ethnic group of the East Slavic peoples, primarily living in Russia and neighboring countries *Rossiyane (), Russian language term for all citizens and peo ...
chemist named
Vladimir Markovnikov Vladimir Vasilyevich Markovnikov (russian: Влади́мир Васи́льевич Марко́вников), also spelled as Markownikoff ( – 11 February 1904), was a Russian chemist. Early life and education Markovnikov studied economics at ...
demonstrated that the addition of HBr to
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s usually but not always resulted in a specific orientation.
Markovnikov's rule In organic chemistry, Markovnikov's rule or Markownikoff's rule describes the outcome of some addition reactions. The rule was formulated by Russian chemist Vladimir Markovnikov in 1870. Explanation The rule states that with the addition of a p ...
, which stems from these observations, states that in the addition of HBr or another hydrogen
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fluor ...
to an alkene, the acidic
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
will add to the less substituted
carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...
of the
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
. This directed addition of a proton results in the more thermodynamically stable
carbocation A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encountere ...
intermediate, as determined by degrees of substitution; more highly substituted carbocations are stabilized by the electron-pushing inductive effect of the surrounding carbon
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
s. Kharasch, in his seminal 1933 paper entitled "The Addition of Hydrogen Bromide to Allyl Bromide", proposed that the anti-Markovnikov addition of HBr to allyl bromide to yield 1,3-dibromopropane was due to the presence of
peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen p ...
s. He termed this the "peroxide effect", which he proposed proceeds through a free radical
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. Chain reactions are one way that syst ...
addition. Elsewhere in the
literature Literature is any collection of written work, but it is also used more narrowly for writings specifically considered to be an art form, especially prose fiction, drama, and poetry. In recent centuries, the definition has expanded to include ...
, 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 A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
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 is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measured with a thermometer. Thermometers are calibrated in various temperature scales that historically have relied o ...
, solvent, or
light Light or visible light is electromagnetic radiation that can be perceived by the human eye. Visible light is usually defined as having wavelengths in the range of 400–700 nanometres (nm), corresponding to frequencies of 750–420 tera ...
affected the orientation of addition only through the chemistry of the peroxides. Once Kharasch began determining the 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 The atmosphere of Earth is the layer of gases, known collectively as air, retained by Earth's gravity that surrounds the planet and forms its planetary atmosphere. The atmosphere of Earth protects life on Earth by creating pressure allowing f ...
or other
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
source), the average reaction time took about 10 days with an approximate yield of 88%, the majority of which was the expected (according to
Markovnikov's rule In organic chemistry, Markovnikov's rule or Markownikoff's rule describes the outcome of some addition reactions. The rule was formulated by Russian chemist Vladimir Markovnikov in 1870. Explanation The rule states that with the addition of a p ...
) 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 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 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 The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no kn ...
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 atom 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 for a proposition is what supports this proposition. It is usually understood as an indication that the supported proposition is true. What role evidence plays and how it is conceived varies from field to field. In epistemology, evidenc ...
. Because he had no means of isolating the proposed
allyl In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
bromide peroxide, he performed an adapted version of the
thiocyanate Thiocyanate (also known as rhodanide) is the anion . It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Mercury(II) thiocyanate was formerly used in pyrot ...
test, an analytical test that is often employed to check shelf-stored
reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
s for their peroxide content.Thiocyanate Colorimetric Determination of Nonmetals, 2nd ed., Vol. 8, p. 304 (1978). In addition to the thiocyanate test, Kharasch further supported the idea of a peroxide-induced
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. Chain reactions are one way that syst ...
by showing that the addition of
antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
s to the reaction mixture caused the reaction to proceed in
aerobic Aerobic means "requiring air," in which "air" usually means oxygen. Aerobic may also refer to * Aerobic exercise, prolonged exercise of moderate intensity * Aerobics, a form of aerobic exercise * Aerobic respiration, the aerobic process of cellu ...
conditions much as it would have if it were ''in vacuo'', 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 In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
. The is that the radical becomes effectively neutralized, while the antioxidant itself becomes a radical. Antioxidants, however, are much less reactive radicals as they are usually rather large and
resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied periodic force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts. When an oscillatin ...
stabilized
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
compounds, and therefore prevent undesired oxidations from occurring. The addition of antioxidants in the reaction mixture in this experiment would effectively
quench In materials science, quenching is the rapid cooling of a workpiece in water, oil, polymer, air, or other fluids to obtain certain material properties. A type of heat treating, quenching prevents undesired low-temperature processes, such as phas ...
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 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 The relative permittivity (in older texts, dielectric constant) is the permittivity of a material expressed as a ratio with the electric permittivity of a vacuum. A dielectric is an insulating material, and the dielectric constant of an insulat ...
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 In physics, the wavelength is the spatial period of a periodic wave—the distance over which the wave's shape repeats. It is the distance between consecutive corresponding points of the same phase on the wave, such as two adjacent crests, tro ...
favored the 1,3- addition, but in the presence of strong antioxidants the
electrophilic addition In organic chemistry, an electrophilic addition reaction is an addition reaction where a chemical compound containing a double or triple bond has a π bond broken, with the formation of two new σ bonds.March, Jerry; (1985). Advanced Organic Che ...
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 In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
reactions of unsaturated
hydrocarbons In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ex ...
were discovered and
mass production Mass production, also known as flow production or continuous production, is the production of substantial amounts of standardized products in a constant flow, including and especially on assembly lines. Together with job production and batch ...
of synthetic rubber and
plastic Plastics are a wide range of synthetic or semi-synthetic materials that use polymers as a main ingredient. Their plasticity makes it possible for plastics to be moulded, extruded or pressed into solid objects of various shapes. This adaptab ...
s was possible. Through similar radical processes, standard
alkanes In organic chemistry, an alkane, or paraffin (a historical trivial name that also has other meanings), is an acyclic saturated hydrocarbon. In other words, an alkane consists of hydrogen and carbon atoms arranged in a tree structure in which ...
are
halogenated In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polyme ...
and made substantially more reactive. This allows them to be very useful intermediates in
organic syntheses ''Organic Syntheses'' is a peer-reviewed scientific journal that was established in 1921. It publishes detailed and checked procedures for the synthesis of organic compounds. A unique feature of the review process is that all of the data and ex ...
. While standard conditions generally support one orientation of addition, in some cases it may be advantageous to have the
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fluor ...
on the less highly substituted carbon, in the anti-Markovnikov position. In this case a
free radical addition In organic chemistry, free-radical addition is an addition reaction which involves free radicals. The addition may occur between a radical and a non-radical, or between two radicals. The basic steps with examples of the free-radical addition (al ...
step may be the key to obtaining the desired ultimate product, and is possible because of the work of Morris Kharasch.


References

"The Peroxide Effect in the Addition of Reagents to Unsaturated Compounds. I. The Addition of Hydrogen Bromide to Allyl Bromide"


External links

* . Accessed 2018-01-12 {{DEFAULTSORT:Karasch 20th-century American chemists Eli Lilly and Company Russian chemists Emigrants from the Russian Empire to the United States Kharasch 1895 births 1957 deaths Ukrainian Jews 20th-century American inventors