Chemical Education Today
Chemistry in the News
1998 Nobel Prizes Chemistry by Jennifer Miller
The Royal Swedish Academy of Sciences has awarded the 1998 Nobel Prize in Chemistry to Walter Kohn (University of California at Santa Barbara) for his development of the density-functional theory and to John A. Pople (Northwestern University at Evanston, Illinois) for his development of computational methods in quantum chemistry. Quantum Mechanics: A Historical Background In order to appreciate the significance of the contributions from this year’s Nobel laureates, we must first realize that near the end of the 19th century the general consensus among physicists was that all principles of physics had been discovered, and little remained to be uncovered. Accomplishments made during the nineteenth century comprise what we now refer to as classical physics: the equivalence of heat and mechanical work as demonstrated by Count Rumford and Joule; Carnot’s second law of thermodynamics; the development of thermodynamics by Gibbs; the study of the effects of electricity and magnetism; and the unification of optics, electricity, and magnetism with Maxwell’s theory of the electromagnetic nature of light. However, classical physics was inadequate in explaining the complex structure of the atom, which became fully appreciated upon three significant discoveries: the electron by Thomson (1897), X-rays by Roentgen (1895), and radioactivity by Becquerel (1896). Early in the 20th century, Einstein completely transformed our ideas of space and time. He proposed that energy and mass are equivalent and that light consists of small, discrete packets (quanta or photons) whose energies depend on their wavelengths. In the 1920s, Schrödinger and Heisenberg introduced the theory of quantum mechanics— a field to be developed over several decades by many people. In quantum mechanics, we see the extension of classical physics to subatomic, atomic, and molecular sizes and distances: primarily that particles have wave-like properties, and the position and momentum of a particle cannot be simultaneously known with infinite precision. The theories of relativity and quantum mechanics constitute what is now called modern physics.
The information about the 1998 Nobel Prizes was adapted from the press releases of the Royal Swedish Academy of Sciences at http://www.nobel.se/announcement-98/ and at http://www.kva.se/. Further information is available from the Academy of Sciences, Information Department, Box 50005, SE-104 05 Stockholm, Sweden; phone: +46 8 673 95 25; fax: +46 8 15 56 70; email:
[email protected].
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A mapping of the electrostatic potential on the HOMO surface for 2-methoxynaphthalene. The dark blue color indicates an area of higher electron density predicting, correctly, that the 1-position of the molecule is the preferred site for reaction by electrophilic reagents.
The laws of quantum mechanics made it theoretically possible to understand and calculate how electrons and atomic nuclei interact to create chemical bonds. This gave rise to the field of quantum chemistry, in which quantum mechanics is applied to chemical problems. However, until the 1960s, it was not feasible to handle the complicated mathematical relations of quantum mechanics for complex systems like molecules. The conventional calculations of molecular properties required determining the motion of each individual electron, and molecules of practical importance contain large numbers of electrons. Many physicists and chemists simply believed that the structures of molecules were too complex for practical application of quantum mechanics. Two developments changed that idea: Kohn’s proof that molecular energies could be calculated from the spatial distribution of electrons, and Pople’s development of software that exploited the ever-increasing calculational power of computers to predict molecular properties and how a chemical reaction takes place. Walter Kohn and the Density-Functional Theory In 1964, Pierre Hohenberg and Walter Kohn proved that the total energy of a system, described by the laws of quantum mechanics, can be theoretically calculated if the electrons’ spatial distribution (or electron density) is known. In collaboration with Lu Sham, Kohn went on to derive a set of equations for determining the ground-state density of an atom. Initially, the equations were used to describe atomic structure, and they were later refined to describe more complicated forms of matter in detail. Calculating the energy of a system in terms of electron density, rather than the motions of each individual electron, greatly simplified the equations for describing the electronic structure of atoms and the nature of the forces that bond them together in molecules. This density-functional theory is now used to study many
Journal of Chemical Education • Vol. 76 No. 1 January 1999 • JChemEd.chem.wisc.edu
Chemical Education Today
types of chemical problems, from calculating the geometrical structures of molecules to explaining the pathways of chemical and enzymatic reactions. John Pople and Computational Chemistry John Pople developed methods for making reliable predictions about the properties of molecular systems by extending the fundamental laws of quantum mechanics and taking advantage of the capabilities of computers. Pople realized that, for theoretical methods to gain any importance in chemistry, it was necessary to know the accuracy of the results in any given case. He created GAUSSIAN, a computer program that reduced the computational costs of calculating integrals, allowed the accuracy of results to be determined, and was reasonably easy for others to use. If the characteristics of a molecule or a chemical reaction are entered into a computer, GAUSSIAN will produce a description of the properties of that molecule or how a chemical reaction may take place. In
1970, the first version of the program was made available, and it was soon used by many chemists to analyze the structure and properties of molecules. Pople continued to refine the methodology; among other things he incorporated the density-functional theory in the 1990s. These developments have resulted in a new set of computational models that can predict molecular structures and properties of chemical reactions. Quantum chemistry is now used in almost all fields of chemistry, especially when the appropriate experiments cannot be performed or when a chemist wants to select from a large number of compounds those for which experiments are most likely to be successful. These theoretical methods also allow for the confirmation and explanation of experimental results. Kohn and Pople’s contributions in understanding chemistry at the molecular level were crucial in advancing the field of quantum chemistry; their developments have permitted the analysis of increasingly more complex molecules.
Medicine The Nobel Assembly at the Karolinska Institute has awarded the 1998 Nobel Prize in Physiology or Medicine jointly to Robert F. Fuchgott (State University of New York Health Science Center at Brooklyn), Louis J. Ignarro (University of California at Los Angeles), and Ferid Murad (University of Texas Medical School at Houston) for identifying nitric oxide as a key biological signaling molecule in the cardiovascular system. Nitric Oxide as a Signaling Molecule Nitrogen is essential to all living systems. However, N2 is an inert molecule and must be transformed into a nitrogen-containing compound in order for an organism to use it. This transformation is known as nitrogen fixation and is required for the synthesis of necessary biomolecules, such as amino acids. One form of fixed nitrogen, nitric oxide (NO), is a common air pollutant that is formed when nitrogen reacts with oxygen, as in the cases of lightning and internal combustion engines. Abundant in air, nitrogen is drawn into the engine of an automobile and reacts at a significant rate with oxygen to form nitric oxide. Nitric oxide is a very unstable molecule that quickly (in less than 10 seconds) changes into nitrate and nitrite under aqueous conditions. Unlike most signaling molecules—such as peptides, proteins, and organic molecules—nitric oxide is a gas. For these reasons, it is particularly surprising that NO can elicit important responses in a living organism. Experimental results have confirmed that NO is a signal molecule. Produced by the enzyme NO synthase in the endothelium cells of arteries, NO diffuses through the membranes and spreads to the underlying muscle cells where it regulates the function of those cells by binding to the enzyme guanylyl cyclase. Once NO binds to guanylyl cyclase, the en-
zyme is activated and starts to produce cyclic guanosine monophosphate (cyclic GMP) from guanosine triphosphate (GTP). The production of cyclic GMP initiates a cascade of events that eventually leads to the activation of myosin, an important component in the process of muscle contraction. The activation of myosin results in the relaxation of the muscle cell and, consequently, the blood vessel dilates or widens. Robert F. Furchgott’s interest in nitric oxide began while he was studying the effects of drugs on blood vessels. These experiments gave him contradictory results: the same drug induced contractions and dilatations of blood vessels. He began to wonder if the variation depended on whether the surface cells (endothelium) inside the blood vessels were intact or damaged. In 1980, he demonstrated that acetylcholine would dilate blood vessels only if the endothelium was intact and concluded that healthy endothelial cells produced an unknown signaling molecule that made vascular smooth muscle cells relax. Furchgott then embarked on a quest to identify this signaling molecule, which he referred to as the endothelium-derived relaxing factor (EDRF). Louis J. Ignarro participated in the quest for identifying the chemical structure of EDRF. He performed a brilliant series of experiments, independently and in collaboration with Robert Furchgott, that culminated in 1986 with the identification of EDRF as nitric oxide. Nitroglycerin as a Therapeutic Agent Heart disease has been responsible for the greatest number of deaths in America every year since 1900, with the exception of 1918. Atherosclerosis, one common form of heart disease, is caused by the buildup of plaques along the inner walls of coronary arteries. These plaques—consisting of cholesterol, inflammatory cells, and fat within a fibrous coat—
JChemEd.chem.wisc.edu • Vol. 76 No. 1 January 1999 • Journal of Chemical Education
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Chemical Education Today
Chemistry in the News can gradually accumulate over a long period of time and reduce the circulation of blood. When a spasm develops in an atherosclerotic artery, the blood flow is further reduced and causes chest pain, a condition known as angina pectoris. It can be treated with nitroglycerin, which dilates constricted arteries and increases blood flow. Ferid Murad discovered that nitroglycerin and related vasodilating compounds release nitric oxide, which, in turn, relaxes smooth muscle cells. He was fascinated by the idea that a gas could regulate important cellular functions and speculated that endogenous factors, such as hormones, might also act through NO. Although experimental data did not exist to confirm his theory, we now know that nerve transmitters and hormones can induce the release of NO by the endothelium.
Signal transmission by a gas presents an entirely new concept for signaling in biological systems. Produced by a variety of cells and found in most living creatures, NO acts as a signal molecule in the nervous and cardiovascular systems, as a weapon against infections, and as a regulator of blood pressure and blood flow to different organs. Ironically, Alfred Nobel, who invented dynamite, was prescribed nitroglycerin for his chest pain when he became ill with heart disease. The treatment of chest pain with nitroglycerin has been known for over a hundred years, but it has taken that long to determine that the beneficial agent released by nitroglycerin is nitric oxide gas. Jennifer Miller is on the editorial staff of the Journal of Chemical Education.
Signaling Pathways by Nitric Oxide in Blood Vessels Aggregating Platelets
Some of the causes and effects of the release of endotheliumderived nitric oxide (NO). Neurotransmitters and hormones bind to specific receptors of endothelial cells to induce the biosynthesis and release of NO. Endothelium-derived NO is a potent, diffusable vasodilator that spreads through the smooth muscle cells of blood vessels and stimulates guanylate cyclase to produce cyclic GMP. When cGMP binds to myosin, the muscle cells relax, allowing the blood vessels to widen or dilate. Aggregating platelets in blood vessels release serotinin and ADP, which activate the cascade of events leading to vasodilation. Upon dilation, blood flow increases and prevents the adherence and accumulation of platelets along the inside wall of blood vessels. In this way, NO inhibits the aggregation of platelets. It has also been shown that increased blood flow (shear stress) from exercise induces the release of NO and maintains healthy arteries. A product of the decomposition of nitroglycerin, nitric oxide directly stimulates the production of cGMP. Some factors that cause a decline in the production of endothelium-derived NO include: aging, regeneration of the endothelium, high cholesterol levels, hypertension, diabetes, and atherosclerosis.
Norepinephrine
Bradykinin
Serotinin
Binds to Receptors of Endothelial Cells
Exercise
Increased Blood Flow (Shear Stress in Vessels) L-Arginine
Acetylcholine
Biosynthesis of NO from L-Arginine Nitroglycerin
Production of cGMP
Vasodilation
Inhibits Proliferation of Endothelial Cells
Inhibits Aggregation of Circulating Platelets
Cross-section of an atherosclerotic coronary artery (left). The walls of these elastic blood vessels are primarily composed of smooth muscle cells, which can relax and contract. Atherosclerosis literally means “hardening of the arteries” and is characterized by the formation of plaque along the inner wall of arteries (shown in yellow). This accumulation of plaque reduces the flow of blood to the heart by narrowing the crosssectional area of the artery (as shown on the left) and can prevent the heart from receiving its required blood, oxygen, and nutrients. When patients suffering from chest pain associated with atherosclerosis receive nitroglycerin, their constricted arteries will dilate, increasing blood flow and alleviating chest pain (as shown on the right).
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Journal of Chemical Education • Vol. 76 No. 1 January 1999 • JChemEd.chem.wisc.edu
