Editing William Lipscomb (section)

==Scientific studies==

Lipscomb 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 big challenge likely to fail,
and then plotted a course of intermediate goals.

===Nuclear magnetic resonance and the chemical shift===
[[File:Lipscomb-NMR-hexaborene-B6H10.png|thumb|right|NMR spectrum of hexaborane B<sub>6</sub>H<sub>10</sub> showing the interpretation of a spectrum to deduce the molecular structure. (click to read details)]]

In this area Lipscomb proposed that:
"... progress in structure determination, for new polyborane species and for substituted [[borane]]s and [[carborane]]s, would be greatly accelerated if the [boron-11] [[nuclear magnetic resonance]] spectra, rather than [[X-ray diffraction]], could be used."<ref name=Lipscomb1977/>
This goal was partially achieved, although X-ray diffraction is still necessary to determine many such atomic structures. The diagram at right shows a typical nuclear magnetic resonance (NMR) spectrum of a borane molecule.

Lipscomb investigated, "... the carboranes, C<sub>2</sub>B<sub>10</sub>H<sub>12</sub>, and the sites of electrophilic attack on these compounds<ref name=Potenza1966Electrophilic/> using nuclear magnetic resonance (NMR) spectroscopy. This work led to [Lipscomb's publication of a comprehensive] theory of chemical shifts.<ref name=Lipscomb1966Shift/> The calculations provided the first accurate values for the constants that describe the behavior of several types of molecules in magnetic or electric fields."<ref name=HutchinsonDictionary2011/>

Much of this work is summarized in a book by Gareth Eaton and William Lipscomb, ''NMR Studies of Boron Hydrides and Related Compounds'',<ref name=Eaton1969/> one of Lipscomb's two books.

===Boron chemistry and the nature of the chemical bond===

In this area Lipscomb originally intended a more ambitious project: "My original intention in the late 1940s was to spend a few years understanding the [[borane]]s, and then to discover a systematic [[Valence (chemistry)|valence]] description of the vast numbers of electron deficient [[intermetallics|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."<ref name=Lipscomb1977PrixNobel/>
Examples of these intermetallic compounds are KHg<sub>13</sub> and Cu<sub>5</sub>Zn<sub>7</sub>.  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 study was not successful, in part because the calculation time required for intermetallic compounds was out of reach in the 1960s, but intermediate goals involving boron bonding were achieved, sufficient to be awarded a Nobel Prize.

[[File:lipscomb diborane b2h6 atomic diagram.png|thumb|right|Atomic diagram of [[diborane]] (B<sub>2</sub>H<sub>6</sub>).]]
[[File:Diborane 02.svg|thumb|right|Bonding diagram of [[diborane]] (B<sub>2</sub>H<sub>6</sub>) showing with curved lines a pair of [[three-center two-electron bond]]s, each of which consists of a pair of electrons bonding three atoms, two boron atoms and a hydrogen atom in the middle.]]

The three-center two-electron bond is illustrated in [[diborane]] (diagrams at right).
In an ordinary covalent bond a pair of electrons bonds two atoms together, one at either end of the bond, the diboare B-H bonds for example at the left and right in the illustrations.
In three-center two-electron bond a pair of electrons bonds three atoms (a boron atom at either end and a hydrogen atom in the middle), the diborane B-H-B bonds for example at the top and bottom of the illustrations.

Lipscomb's group did not propose or discover the three-center two-electron bond,
nor did they develop formulas that give the proposed mechanism.
In 1943, [[H. Christopher Longuet-Higgins|Longuet-Higgins]], while still an undergraduate at Oxford, was the first to explain
the structure and bonding of the boron hydrides. The paper reporting the work, written with his tutor R. P. Bell,
<ref>{{Cite journal | last1 = Longuet-Higgins | first1 = H. C. | last2 = Bell            | first2 = R. P. | author-link = H. Christopher Longuet-Higgins | title   = 64. The Structure of the Boron Hydrides | journal = Journal of the Chemical Society (Resumed) | year    = 1943 | volume  = 1943 | pages   = 250–255 | doi     = 10.1039/JR9430000250 }}</ref> also reviews the history of the subject beginning with the work of Dilthey.
<ref name=Dilthey1921/> Shortly after, in 1947 and 1948, experimental spectroscopic work was performed by Price<ref name=Price1947/><ref name=Price1948/>
that confirmed Longuet-Higgins' structure for diborane. The structure was re-confirmed by electron diffraction measurement in 1951 by K. Hedberg and V. Schomaker, with the confirmation of the structure shown in the schemes on this page.<ref>{{ cite journal |author1=Hedberg, K. |author2=Schomaker, V. | title = A Reinvestigation of the Structures of Diborane and Ethane by Electron Diffraction | journal = [[Journal of the American Chemical Society]] | year = 1951 | volume = 73 | issue = 4 | pages = 1482–1487 | doi = 10.1021/ja01148a022 }}</ref> Lipscomb and his graduate students further determined the [[molecular structure]] of [[borane]]s (compounds of boron and hydrogen) using [[X-ray crystallography]] in the 1950s and developed theories to explain their [[chemical bond|bond]]s. Later he applied the same methods to related problems, including the structure of [[carborane]]s (compounds of carbon, boron, and hydrogen). [[H. Christopher Longuet-Higgins|Longuet-Higgins]]
and Roberts<ref name=Longuet-Higgins1954/><ref name=Longuet-Higgins1955/>
discussed the electronic structure of an icosahedron of boron atoms and of the borides MB<sub>6</sub>. The mechanism of the three-center two-electron bond was also discussed in a later paper by Longuet-Higgins,<ref>{{cite journal | author1 = H. C. Longuet-Higgins | title = title unknown | journal =  J. Roy. Inst. Chem.| year = 1953 | volume = 77 | page = 197}}</ref> and an essentially equivalent mechanism was proposed by Eberhardt, Crawford, and Lipscomb.<ref name=Eberhardt1954ThreeCenter/>
Lipscomb's group also achieved an understanding of it through electron orbital calculations using formulas by Edmiston and Ruedenberg and by Boys.<ref name=Kleir1974Rudenberg/>

The Eberhardt, Crawford, and Lipscomb paper<ref name=Eberhardt1954ThreeCenter/> discussed above  also devised the "[[styx rule]]" method to catalog certain kinds of boron-hydride bonding configurations.

[[File:lipscomb diamond-square-diamond-horizontal.png|thumb|left|Diamond-square-diamond (DSD) rearrangement. At each vertex is a boron atom and (not shown) a hydrogen atom. A bond joining two triangular faces breaks to form a square, and then a new bond forms across opposite vertices of the square.]]

Wandering atoms was a puzzle solved by Lipscomb<ref name=Lipscomb1966DSD/> in one of his few papers with no co-authors.
Compounds of boron and hydrogen tend to form closed cage structures.
Sometimes the atoms at the vertices of these cages move substantial distances with respect to each other.
The diamond-square-diamond mechanism (diagram at left) was suggested by Lipscomb to explain this rearrangement of vertices.
Following along in the diagram at left for example in the faces shaded in blue,
a pair of triangular faces has a left-right diamond shape.
First, the bond common to these adjacent triangles breaks, forming a square,
and then the square collapses back to an up-down diamond shape
by bonding the atoms that were not bonded before.
Other researchers have discovered more about these rearrangements.<ref>{{cite journal|last=Hutton|first=Brian W. |author2=MacIntosh, Fraser |author3=Ellis, David |author4=Herisse, Fabien |author5=Macgregor, Stuart A. |author6=McKay, David |author7=Petrie-Armstrong, Victoria |author8=Rosair, Georgina M. |author9=Perekalin, Dmitry S. |author10=Tricas, Hugo |author11=Welch, Alan J. |title=Unprecedented steric deformation of ortho-carborane|journal=Chemical Communications |date=2008|issue=42|pages=5345–5347|doi=10.1039/B810702E|pmid=18985205 |url=http://pubs.rsc.org/en/Content/ArticleLanding/2008/CC/b810702e}}</ref>
<ref name=Hosmane1996DSD/>

[[File:Lipscomb b10-h16-horizontal.png|thumb|right|B<sub>10</sub>H<sub>16</sub> showing in the middle a bond directly between two boron atoms without terminal hydrogens, a feature not previously seen in other boron hydrides.]]

The B<sub>10</sub>H<sub>16</sub> structure (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.<ref name=Grimes1961/>

Lipscomb's group developed calculation methods, both empirical<ref name=Eaton1969/> and from quantum mechanical theory.<ref name=Pitzer1962/><ref name=Stevens1963/>
Calculations by these methods produced accurate [[Hartree–Fock method|Hartree–Fock self-consistent field (SCF)]] [[molecular orbital]]s and were used to study boranes and carboranes.

[[File:Lilpscomb-ethane-barrier.png|thumb|left|Ethane barrier to rotation about the carbon-carbon bond, first accurately calculated by Pitzer and Lipscomb.]]

The [[ethane]] barrier to rotation (diagram at left) was first calculated accurately by [[Russell M. Pitzer|Pitzer]] and Lipscomb<ref name=Pitzer1963Ethane/> using the [[Hartree–Fock method|Hartree–Fock (SCF)]] method.

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]]."<ref name=Lipscomb1977/>
This included "... proposed molecular orbital descriptions in which the bonding electrons are delocalized over the whole molecule."<ref name="autogenerated1">{{cite journal | doi = 10.1036/1097-8542.109100| title = Carborane |journal=AccessScience |last=Getman |first=Thomas D. |year=2014}}</ref>

"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,..."<ref name="autogenerated1"/>

Subsequent [[Nobel Prize in Chemistry|Nobel Prize]] winner [[Roald Hoffmann]] was a doctoral student
<ref name=Hoffmann1962TheoryIII/>
<ref name=Hoffmann1962TheoryI/>
<ref name=Hoffmann1962LCAO/>
<ref name=Hoffmann1962Sequential/>
<ref name=Hoffmann1963Carboranes/>
in Lipscomb's laboratory.
Under Lipscomb's direction the [[Extended Hückel method]] of molecular orbital calculation was developed by Lawrence Lohr<ref name=Lipscomb1977PrixNobel/> and by Roald Hoffmann.<ref name=Hoffmann1962TheoryI/><ref name=Lipscomb1963/>  This method was later extended by Hoffman.<ref name=Hoffmann1963/>
In Lipscomb's laboratory this method was reconciled with [[Hartree–Fock method|self-consistent field (SCF)]] theory by Newton<ref name=Newton1966/> and by Boer.<ref name=Boer1966/>

Noted boron chemist [[M. Frederick Hawthorne]] conducted early<ref name=LipscombHawthorne1959/><ref name=PitochelliHawthorne1962/> and continuing<ref name=LipscombHawthorne1972/><ref name=PaxtonHawthorne1974/> research with Lipscomb.

Much of this work is summarized in a book by Lipscomb, ''Boron Hydrides'',<ref name=Lipscomb1963/> 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".<ref>{{cite web|url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1976/ |title=The Nobel Prize in Chemistry 1976 |publisher=Nobelprize.org |access-date=2012-02-01}}</ref>
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."<ref>{{cite web|url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1954/ |title=The Nobel Prize in Chemistry 1954 |publisher=Nobelprize.org |access-date=2012-02-01}}</ref>

The source for about half of this section is Lipscomb's Nobel Lecture.<ref name=Lipscomb1977/><ref name=Lipscomb1977PrixNobel/>

===Large biological molecule structure and function===

Lipscomb's later research focused on the atomic structure of [[protein]]s, 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<ref>{{cite web|url=http://www.rcsb.org/ |title=rcsb.org |publisher=rcsb.org |access-date=2012-02-01}}</ref> 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.

[[File:Carboxypeptidase-a-pdb-5CPA.png|thumb|upright|left|alt=carboxypeptidase A|[[carboxypeptidase A]]]]

[[Carboxypeptidase A]]<ref name=Lipscomb1968CPA/> (left) 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.

[[File:Apartate-carbamoyltransferase-pdb-2ATC.png|thumb|upright|right|alt=apartate carbamoyltransferase|[[aspartate carbamoyltransferase]]]]

[[Aspartate carbamoyltransferase]].<ref name=Honzatko1983atcase/>  (right) was the second protein structure from Lipscomb's group.
For a copy of [[DNA]] to be made, a duplicate set of its [[nucleotide]]s 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.

[[File:Leucine-aminopeptidase-pdb-1LAP..png|thumb|upright|left|alt=leucine aminopeptidase|[[Leucyl aminopeptidase|Leucine aminopeptidase]]]]

[[Leucyl aminopeptidase|Leucine aminopeptidase]],<ref name=Burley1992Bestatin/> (left) a little like carboxypeptidase A, chops off certain amino acids one-by-one from one end of a protein or [[peptide]].

[[File:HaeIII-methyltransferase-dna-pdb-1DCT.png|thumb|upright|right|alt=HaeIII methyltransferase|HaeIII [[methyltransferase]] convalently complexed to DNA]]

HaeIII [[methyltransferase]]<ref name=Reinisch1995methyltransferase/> (right)
binds to DNA where it [[Methylation|methylates]] (adds a methy group to)
it.

[[File:Human-interferon-beta-pdb-1AU1.png|thumb|upright|left|alt=human interferon beta|human [[interferon]] beta]]

Human [[interferon]] beta<ref name=Karpusas1997Interferon/> (left)
is released by [[lymphocyte]]s in response to [[pathogen]]s to trigger the [[immune system]].

[[File:Chorismate-mutase-pdb-2CHS.png|thumb|upright|right|alt=chorismate mutase|[[chorismate mutase]]]]

[[Chorismate mutase]]<ref name=Strater1997chorismate/> (right)
[[catalysis|catalyzes]] (speeds up) the production of the amino acids [[phenylalanine]] and [[tyrosine]].

[[File:Fructose-1.6-bisphosphatase-pdb-3FBP.png|thumb|upright|left|alt=fructose-1,6-bisphosphatase|[[Fructose 1,6-bisphosphatase|fructose-1,6-bisphosphatase]]]]

[[Fructose 1,6-bisphosphatase|Fructose-1,6-bisphosphatase]]<ref name=Ke1989Fructose/> (left)
and its inhibitor MB06322 (CS-917)<ref name=Erion2005Dibetes/>
were studied by Lipscomb's group in a collaboration, which included Metabasis Therapeutics, Inc., acquired by [[Ligand Pharmaceuticals]]<ref>{{cite web|url=http://www.ligand.com/ |title=ligand.com |publisher=ligand.com |access-date=2012-02-01}}</ref> in 2010, exploring the possibility of finding a treatment for [[Diabetes mellitus type 2|type 2 diabetes]], as the MB06322 inhibitor slows the production of sugar by fructose-1,6-bisphosphatase.

{{Clear}}
Lipscomb's group also contributed to an understanding of
[[concanavalin A]]<ref name=Quiocho1971ConA/> (low resolution structure),
[[glucagon]],<ref name=Haugen1969Glucagon/> and
[[carbonic anhydrase]]<ref name=Liang1991Carbonic/> (theoretical studies).

Subsequent [[Nobel Prize in Chemistry|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,<ref name=Steitz1965MEPhosphate/> Steitz made contributions to determining the atomic structures of [[carboxypeptidase A]]
<ref name=Lipscomb1968CPA/>
<ref name=Hartsuck1965CPA/>
<ref name=Lipscomb1965CPA/>
<ref name=Ludwig1966CPA/>
<ref name=Ludwig1967CPA/>
<ref name=Reeke1967CPA/>
<ref name=Lipscomb1967CPA/>
<ref name=Copolla1968CPA/>
and [[aspartate carbamoyltransferase]].
<ref name=Steitz1967ACTase/>
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 in Chemistry|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.<ref name=CEN_Nov_2009/>  This was while she was a postdoctoral student at MIT in 1970.

===Other results===
[[File:Lipscombite sample.jpg|thumb|right|[[Lipscombite]]: Mineral, small green crystals on quartz, [[Harvard Museum of Natural History]], gift of W. N. Lipscomb Jr., 1996]]

The mineral [[lipscombite]] (picture at right) was named after Professor Lipscomb by the mineralogist John Gruner who first made it artificially.

Low-temperature x-ray diffraction was pioneered in Lipscomb's laboratory<ref name=Abrahams1950/><ref name=King1950LowTemperature/><ref name=Milberg1951LowTemperature/> at about the same time as parallel work in [[Isadore Fankuchen]]'s laboratory<ref name=Kaufman1949/> at the then [[Polytechnic Institute of New York University|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.

Other important compounds were studied by Lipscomb and his students.
Among these are
[[hydrazine]],<ref name=Collin1951Hydrazine/>
[[nitric oxide]],<ref name=Dulmage1951Nitric/>
[[metal dithiolene complex|metal-dithiolene complexes]],<ref name=Enemark1965MetalDi/>
methyl ethylene phosphate,<ref name=Steitz1965MEPhosphate/>
mercury [[amide]]s,<ref name=Lipscomb1957Mercury/>
(NO)<sub>2</sub>,<ref name=Lipscomb1971NO2/>
crystalline [[hydrogen fluoride]],<ref name=Atoji1954HF/>
[[Roussin's black salt]],<ref name=Johansson1958Roussin/>
(PCF<sub>3</sub>)<sub>5</sub>,<ref name=Spencer1961PCF/>
complexes of [[Cyclooctatetraene|cyclo-octatetraene]] with [[(Benzylideneacetone)iron tricarbonyl|iron tricarbonyl]],<ref name=Dickens1962Octatetraene/>
and [[Vincristine|leurocristine (Vincristine)]],<ref name=Moncrief1965Vincristine/> which is used in several cancer therapies.