William Nunn Lipscomb, Jr. was a Nobel Prize-winning
American inorganic and
organic chemist working in
nuclear magnetic resonance,
theoretical chemistry,
boron chemistry, and biochemistry died from pneumonia he was , 91.
(December 9, 1919 – April 14, 2011)
Biography
Lipscomb was born in
Cleveland, Ohio. His family moved to
Lexington, Kentucky in 1920,
[1] and he lived there until he received his
Bachelor of Science degree in Chemistry at the
University of Kentucky in 1941. He went on to earn his
Doctor of Philosophy degree in Chemistry from the
California Institute of Technology in 1946.
From 1946 to 1959 he taught at the
University of Minnesota. From 1959 to 1990 he was a professor of
chemistry at
Harvard University, where he was a
professor emeritus since 1990.
Lipscomb resided in
Cambridge, Massachusetts until his death in 2011 from
pneumonia.
Scientific studies
Lipscomb has worked in three main areas, nuclear magnetic resonance and the chemical shift, boron chemistry and the nature of the chemical bond, and large biochemical molecules. These areas overlap in time and share some scientific techniques. In at least the first two of these areas Lipscomb gave himself a grand challenge likely to fail, and then plotted a course of intermediate goals.
Nuclear Magnetic Resonance and the Chemical Shift
In this area Lipscomb gave himself this grand challenge: "I thought then that progress in structure determination, for new polyborane species and for substituted
boranes and
carboranes, would be greatly accelerated if the [boron-11]
nuclear magnetic resonance spectra, rather than
X-ray diffraction, could be used."
[3] This grand challenge was not successful, as X-ray diffraction is still necessary to determine many such atomic structures, but intermediate goals were achieved:
Nuclear magnetic resonance spectroscopy uses
Nuclear Magnetic Resonance (NMR) to produce spectra (see diagram at left) consisting of clues to the atomic structure of molecules. The magnetic energy of atomic nuclei produce peaks, which shift slightly in the spectrum graph depending on the electronic influences of nearby atoms. This
chemical shift suggests what kinds of atoms are close to what other kinds of atoms, which, when combined with the sizes and shapes of the peaks, gives clues to the three-dimensional structure of the molecule.
Lipscomb investigated, "... the carboranes, C
2B
10H
12, and the sites of electrophilic attack on these compounds
[4] using nuclear magnetic resonance (NMR) spectroscopy. This work led to [Lipscomb's publication of a comprehensive] theory of chemical shifts.
[5] The calculations provided the first accurate values for the constants that describe the behavior of several types of molecules in magnetic or electric fields."
[2]
Much of this work is summarized in a book by Gareth Eaton and William Lipscomb,
NMR Studies of Boron Hydrides and Related Compounds,
[6] one of Lipscomb's two books.
Boron Chemistry and the Nature of the Chemical Bond
In this area Lipscomb gave himself this grand challenge: "My original intention in the late 1940’s was to spend a few years understanding the
boranes, and then to discover a systematic
valence description of the vast numbers of electron deficient
intermetallic compounds. I have made little progress toward this latter objective. Instead, the field of
boron chemistry has grown enormously, and a systematic understanding of some of its complexities has now begun."
[7] Examples of these intermetallic compounds are KHg
13 and Cu
5Zn
7. Of perhaps 24,000 of such compounds the structures of only 4,000 are known (in 2005) and we cannot predict structures for the others, because we do not sufficiently understand the nature of the chemical bond. This grand challenge was not successful, in part because the calculation time required for intermetallic compounds was out of reach in the 1960s, but intermediate goals were achieved, sufficient to be awarded a Nobel Prize.
Lipscomb deduced the
molecular structure of
boranes (compounds of boron and hydrogen) using
X-ray crystallography in the 1950s and developed theories to explain their
bonds. Later he applied the same methods to related problems, including the structure of
carboranes (compounds of carbon, boron, and hydrogen).
Diborane is a simple molecule (see diagrams at right) that illustrates some of Lipscomb's contributions to understanding the nature of the chemical bond. Over several decades the structure and bonding arrangement was gradually discovered by Dilthey,
[8] Price,
[9][10] and others. In an ordinary covalent bond a pair of electrons bonds two atoms together, one at either end of the bond.
Longuet-Higgins and Roberts
[11] [12] employed a
three-center two-electron bond, in which a pair of electrons bonds three atoms (a boron atom at either end and a hydrogen atom in the middle), as the correct way to understand bonding in diborane using a molecular orbital description similar to what the Lipscomb group found. Eberhardt, Crawford, and Lipscomb proposed the mechanism
[13] of the three-center two-electron bond, and Lipscomb's group achieved an understanding of it through electron orbital calculations using formulas by Edmiston and Ruedenberg and by Boys.
[14] The Eberhardt, Crawford, and Lipscomb paper
[13] also devised the "styx number" method to catalog certain kinds of boron-hydride bonding configurations. Going letter-by-letter through "styx", "s" is the number of BHB bonds, "t" is the number of BBB bonds, "y" is the number of BB bonds, and "x" is the number of terminal BH
2 groups, so for example the molecule diborane can be described by a styx number of 2002 (2 BHB bonds and 2 BH
2 groups). Only some styx numbers are possible, subject to certain molecular orbital constraints for which Eberhardt, Crawford, and Lipscomb devised simple equations for any given boron hydride B
pH
q, for example, for three-center orbital balance 4p = (q - s) + 2s + 3t + 2y and for electron balance 3p = (q - s) + s + 2(t + y).
[3]
The diamond-square-diamond
[15] mechanism (see diagram at left) was suggested by Lipscomb to explain the rearrangement of BH and CH vertices in polyhedral
closo-boranes and closo-carboranes. Two adjacent triangular faces, forming a diamond shape, break the central bond to form a square, and reconnect the alternate vertices to form another diamond shape. The DSD diagram at right shows the first two steps of rearrangement in
this link. Lipscomb proposed that conversion of the ortho-carborane involves six simultaneous DSD processes that give rise to a
cuboctahedron, which can then collapse to give the "carbons apart" meta-carborane. Despite the general acceptance of the DSD process, there is not agreement on the mechanism of the
isomerization of the
icosahedral carboranes or on the viability of the cuboctahedron as an intermediate, though the ortho- to meta-carborane isomerization process was described more recently through multiple DSD processes alone and is currently the lowest energy process known.
[16] The crystal structure of the cuboctahedron geometry was later confirmed
[17] by his long-time collaborator,
Narayan Hosmane.
The B
10H
16 structure (see diagram at right) determined by Grimes, Wang, Lewin, and Lipscomb found a bond directly between two boron atoms without terminal hydrogens, a feature not previously seen in other boron hydrides.
[18]
Lipscomb's group developed calculation methods, both empirical
[6] and from quantum mechanical theory.
[19][20] Calculations by these methods produced accurate
self-consistent field (SCF) molecular orbitals and were used to study boranes and carboranes.
The
ethane barrier (see diagram at left) was first calculated accurately by
Pitzer and Lipscomb
[21] also using
Hartree Fock Self-Consistent Field (SCF) theory. Ethane gives a classic, simple example of such a
rotational barrier, the minimum energy to produce a 360-degree bond rotation of a molecular substructure. The three hydrogens at each end are free to pinwheel about the central carbon-carbon bond, provided that there is sufficient energy to overcome the barrier of the carbon-hydrogen bonds at each end of the molecule bumping into each other by way of overlap (exchange) repulsion.
Lipscomb's calculations continued to a detailed examination of partial bonding through "... theoretical studies of multicentered chemical bonds including both delocalized and localized molecular orbitals."
[3] This included "... proposed molecular orbital descriptions in which the bonding electrons are delocalized over the whole molecule."
[4]
"Lipscomb and his coworkers developed the idea of transferability of atomic properties, by which approximate theories for complex molecules are developed from more exact calculations for simpler but chemically related molecules, ...."
[5]
Subsequent
Nobel Prize winner
Roald Hoffmann was a doctoral student
[22] [23] [24] [25] [26] in Lipscomb's laboratory. Under Lipscomb's direction the
Extended Huckel method of molecular orbital calculation was developed by Lawrence Lohr
[6] and by Roald Hoffmann.
[23][27] This method was later extended by Hoffman.
[28] In Lipscomb's laboratory this method was reconciled with
self-consistent field (SCF) theory by Newton
[29] and by Boer.
[30]
Noted boron chemist
M. Frederick Hawthorne conducted early
[31][32] and continuing
[33][34] research with Lipscomb.
Much of this work is summarized in a book by Lipscomb,
Boron Hydrides,
[27] one of Lipscomb's two books.
The 1976
Nobel Prize in Chemistry was awarded to Lipscomb "for his studies on the structure of boranes illuminating problems of chemical bonding".
[7] In a way this continued work on the nature of the chemical bond by his Doctoral Advisor at the California Institute of Technology,
Linus Pauling, who was awarded the 1954 Nobel Prize in Chemistry "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances."
[8]
Large Biological Molecule Structure and Function
Lipscomb's later research focused on the atomic structure of
proteins, particularly how
enzymes work. His group used x-ray diffraction to solve the three-dimensional structure of these proteins to atomic resolution, and then to analyze the atomic detail of how the molecules work.
The images below are of Lipscomb's structures from the Protein Data Bank
[9] displayed in simplified form with atomic detail suppressed. Proteins are chains of amino acids, and the continuous ribbon shows the trace of the chain with, for example, several amino acids for each turn of a helix.
Carboxypeptidase A [35] was the first protein structure from Lipscomb's group. Carboxypeptidase A is a digestive enzyme, a protein that digests other proteins. It is made in the pancreas and transported in inactive form to the intestines where it is activated. Carboxypeptidase A digests by chopping off certain amino acids one-by-one from one end of a protein. The size of this structure was ambitious. Carboxypeptidase A was a much larger molecule than anything solved previously.
Aspartate carbamoyltransferase.
[36] was the second protein structure from Lipscomb's group. For a copy of
DNA to be made, a duplicate set of its
nucleotides is required. Aspartate carbamoyltransferase performs a step in building the
pyrimidine nucleotides (
cytosine and
thymidine). Aspartate carbamoyltransferase also ensures that just the right amount of pyrimidine nucleotides is available, as activator and inhibitor molecules attach to aspartate carbamoyltransferase to speed it up and to slow it down. Aspartate carbamoyltransferase is a complex of twelve molecules. Six large catalytic molecules in the interior do the work, and six small regulatory molecules on the outside control how fast the catalytic units work. The size of this structure was ambitious. Aspartate carbamoyltransferase was a much larger molecule than anything solved previously.
Leucine aminopeptidase,
[37] a little like carboxypeptidase, chops off certain amino acids one-by-one from one end of a protein or
peptide. It seems to play a role in reprocessing old molecules into new inside a cell. A version of leucine aminopeptidase has been shown to play a roll in regulating plant immune response and response to wounding.
HaeIII
methyltransferase[38] binds to DNA where it recognises and
methylates (adds a methy group to) the central
cytosine in the DNA sequence GGCC.
DNA methylation is often used to silence and regulate genes without changing the original DNA sequence, an example of
epigenetic modification. This methylation occurs on cytosine residues.
DNA methylation may be necessary for normal growth from embryonic stages in mammals.
[39] Methylation may also be linked to cancer development as methylation of tumor suppressor genes promotes tumorgenesis and
metastasis.
[40] Methylation can also serve to protect DNA from enzymatic cleavage, since restriction enzymes are unable to bind and recognize externally modified sequences. This is especially useful in bacterial
restriction modification systems that use restriction enzymes to cleave foreign DNA while keeping their own DNA protected by methylation.
Human
interferon beta
[41] is a member of the
interferon family of molecules. Interferons are
proteins made and released by
lymphocytes in response to the presence of
pathogens—such as
viruses,
bacteria, or
parasites—or
tumor cells. They allow communication between cells to trigger the protective defenses of the
immune system that eradicate pathogens or tumors. Interferons belong to the large class of
glycoproteins known as
cytokines. Interferons are named after their ability to "interfere" with
viral replication within host cells. Interferons have other functions: they activate immune cells, such as
natural killer cells and
macrophages; they increase recognition of infection or tumor cells by up-regulating
antigen presentation to
T lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such as aching muscles and fever, are related to the production of interferons during infection. The drug
interferon beta-1a is used to treat
multiple sclerosis (MS).
Chorismate mutase[42] is an
enzyme that
catalyzes (speeds up) the
chemical reaction for the conversion of
chorismate to
prephenate in the pathway leading to the production of the amino acids
phenylalanine and
tyrosine, which may then be used to make proteins.
Fructose-1,6-bisphosphatase [43] and its inhibitor MB06322 (CS-917)
[44] were studied by Lipscomb's group in a collaboration, which included Metabasis Therapeutics, Inc., acquired by
Ligand Pharmaceuticals in 2010, exploring the possibility of finding a treatment for
type 2 diabetes, as the MB06322 inhibitor slows the production of sugar by fructose-1,6-bisphosphatase. Fructose-1,6-bisphosphatase is an
enzyme in the
liver that converts
fructose-1,6-bisphosphate to
fructose 6-phosphate in
gluconeogenesis (the synthesis of
glucose from smaller substrates). Fructose bisphosphatase
catalyses the reverse of the reaction which is catalysed by
phosphofructokinase, which is involved in the process of
glycolysis. These enzymes only catalyse the reaction in one direction each, and are regulated by metabolites such as
fructose 2,6-bisphosphate so that high activity of one of the two enzymes is accompanied by low activity of the other.
(Much of the text above describing these large molecules is copied from Wikipedia pages about them.)
Lipscomb's group also contributed to an understanding of
concanavalin A[45] (low resolution structure),
glucagon,
[46] and
carbonic anhydrase[47] (theoretical studies).
Subsequent
Nobel Prize winner
Thomas A. Steitz was a doctoral student in Lipscomb's laboratory. Under Lipscomb's direction after the training task of determining the structure of the small molecule methyl ethylene phosphate,
[48] Steitz made contributions to determining the atomic structures of
carboxypeptidase A [35] [49] [50] [51] [52] [53] [54] [55] and
aspartate carbamoyltransferase.
[56] Steitz was awarded the 2009
Nobel Prize in Chemistry for determining the even larger structure of the large
50S ribosomal subunit, leading to an understanding of possible medical treatments.
Subsequent
Nobel Prize winner
Ada Yonath, who shared the 2009 Nobel Prize in Chemistry with
Thomas A. Steitz and
Venkatraman Ramakrishnan, spent some time in Lipscomb's lab where both she and Steitz were inspired to pursue later their own very large structures.
[57] This was while she was a postdoctoral student at MIT in 1970.
Other Results
The mineral lipscombite
[58] [10] [11] (see picture at right) was named after Professor Lipscomb by the geologist John Gruner who created it. It was the second mineral to be first made artificially and then discovered in nature. John Gruner, geology professor at the University of Minnesota, was trying to make
phosphate minerals in a pressure-inducing metal ball, but materials in the ball contaminated the sample. The x-ray
powder diffraction pattern was close to what the geologists wanted, but unknown. Powder diffraction is limited to identifying an unknown sample as some specific known substance or as not a known substance in the catalog. Lipscomb was therefore invited to determine the atomic structure using
single-crystal x-ray diffraction. Lipscomb found the sample to be an iron phosphate mineral but with manganese and
tetragonal instead of the usual
monoclinic.
Low-temperature x-ray diffraction was pioneered in Lipscomb's laboratory
[59][60][61] at about the same time as parallel work in Isadore Fankuchen’s laboratory
[62] at the then
Polytechnic Institute of Brooklyn. Lipscomb began by studying compounds of nitrogen, oxygen, fluorine, and other substances that are solid only below liquid nitrogen temperatures, but other advantages eventually made low-temperatures a normal procedure. Keeping the crystal cold during data collection produces a less-blurry 3-D electron-density map because the atoms have less thermal motion. Crystals may yield good data in the x-ray beam longer because x-ray damage may be reduced during data collection and because the solvent may evaporate more slowly, which for example may be important for large biochemical molecules whose crystals often have a high percentage of water.
Many other important compounds were studied by Lipscomb and his students. Most notable among these are
hydrazine,
[63] nitric oxide,
[64] metal-dithiolene complexes,
[65] methyl ethylene phosphate,
[48] mercury
amides,
[66] (NO)
2,
[67] crystalline
hydrogen fluoride,
[68] Roussin's black salt,
[69] (PCF
3)
5,
[70] complexes of
cyclo-octatetraene with
iron tricarbonyl,
[71] and
leurocristine (Vincristine),
[72] which is used in several cancer therapies.
Other Awards and Activities
The Colonel is how Lipscomb's students referred to him, directly addressing him as Colonel. "His first doctoral student, Murray Vernon King, pinned the label on him, and it was quickly adopted by other students, who wanted to use an appellation that showed informal respect. ... Lipscomb's Kentucky origins as the rationale for the designation."
[77] Some years later in 1973 Lipscomb was made a member of the
Honorable Order of Kentucky Colonels.
[78]
Three books and published symposia are dedicated to Lipscomb,
Structures and Mechanisms: From Ashes to Enzymes,
[79] Proceedings of the International Symposium on Quantum Chemistry, Solid-State Theory and Molecular Dynamics,
[80] and
Electron Deficient Boron and Carbon Clusters.
[81]
Lipscomb, along with several other Nobel laureates, is a regular presenter at the annual
Ig Nobel Awards Ceremony, most recently doing so on September 30, 2010.
[12]
To see more of who died in 2010 click here
In 1960, Bannister appeared on stage at the Cambridge Theatre in London in Billy Liar, which starred Albert Finney. He starred as Darkie Pilbeam, a wartime spiv, in the 1968 television series The War of Darkie Pilbeam, and from 1969 to 1970 he appeared as "Heavy Breathing" in Jack Rosenthal's sitcom, The Dustbinmen. Shortly afterwards, he was asked to play Mr Lucas in a Comedy Playhouse pilot called Are You Being Served? and took the part in the series.[3]
