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Applications of X-ray Crystallographic Techniques. A tool to help answer chemical questions 1
presentsSpecial Topics Course 913
Richard J. Staples, Ph.D.Senior Academic Specialist of X-ray CrystallographyDepartment of Chemistry
Senior Academic Specialist of X-ray Crystallography Michigan State University, Department of Chemistry
Lab Chemistry 434, 582Office Chemistry 418A
Phone: (517) 353-1074EMAIL: [email protected]
Dr. Richard J. Staples
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• Ph.D., Chemistry; December 1989. The University of Toledo
• Post-doc Texas A&M University, John P. Fackler,Head of Research Group
Inorganic chemistry, transition metals• University Crystallographer, University of Idaho.
Operated one of the first SMART CCD Diffractometers• Harvard University, 1997-2007• Joined Michigan State University in July 2007.
Educational History
Course Outline Theory and basics of X-ray Diffraction Specifics and practical of Single Crystal diffraction
Specifics and practical of Macromolecular diffraction
Specifics and practical of Powder/ Material diffraction
LAB Portion
Single crystal solving
Data base searching
Powder diffraction solving
Macromolecular workings
Test, Midterm and Final
Homework Assignments, count as a third test.
Solve one Structure to publication quality or some lab project,
can not get credit if not completed.
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Text Books Dealing with X-ray Diffraction and Structure Analysis Single Crystal
Textbook and Requirements
Required Text Single Crystal Diffraction:”Crystal
Structure Determination” W. Massa ISBN: 3-540-
65970-6
Recommend: “Chemical Applications of Group
Theory” F. A. Cotton, 3rd edition.
Recommend: “International Tables for
Crystallography, Brief Teaching Edition of Volume A.”Kluwer Academic Publishers.
Text Books Dealing with X-ray Diffraction and Structure Analysis Macromolecular
Required Text Macromolecular
Crystallography:”Crystallography Made Crystal
Clear” 2nd edition, A guide for users of
Macromolecular Models, G. Rhodes ISBN: 0-12-
587072-8
Other: “Principles of Protein X-ray Crystallography” 2
nd edition, Jan Drenth ISBN:0-387-98587-5
Protein Crystallization, Techniques, Strategies, and Tips
( A Laboratory Manual) Terese M. Bergfors ISBN: 0-
9636817-5-3
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Text Books Dealing with X-ray Diffraction and Structure
Analysis Powder Required Text Powder Diffraction:”Fundamentals of
Powder Diffraction and Structural Characterization”Vitalij Pecharsky and Peter Y. Zavalij, 2nd edition
ISBN: 978-0-387-09578-3
Recommend: “Principles and Applications of Powder
Diffraction”A. Clearfield, J. Reibenspies, N Bhuvanesh
ISBN: 978-1-4051-6222-7
Recommend: “Structure Determination from Powder
Diffraction Data” W.I.F. David, K.Shankland, L.B.
McCuster and Ch. Baerlocher ; IUCr Monographs on
Crystallography ISBN: 0-19-850091-2
Detailed Outline ZOOM Meeting Tuesday, Thursday 12:40-2:00 P.M. NO Spring Break Week, Note 2 days off at different time. I plan to be in most mornings in the Chemistry
Department for questions. Contact me if you need help!!!!!!!!
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NEED To Complete Project Before end of Semester
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Applications of X-ray Crystallographic Techniques. A tool to help answer chemical questions
Dr. Richard J. StaplesMichigan State University Center For Crystallographic Research
The GoalEnlighten the Audience as to the vast and interesting results and Chemistry one can see because of crystallography.
Help to provide an understanding of why crystallography is so important.
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What is a crystal structure? The determination of the connectivity of the atoms in
a compound and the way the molecule (or molecules) pack to form a solid crystalline material.
Exact connectivity. Bond distances and angles. Complete identification of the compound. Identification of lattice.
What is gained from a crystal structure?
Positive identification of a single crystal. Exact connectivity. Bond distances and angles. Complete identification of the compound. Inter molecular interactions. Intra molecular interactions.
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History of Crystallography? Early work, 1756, focused on properties of light through
crystals, hardness, and shape of crystals.
Minerals from waterBy Shape
NaCl and CaCO3
X-rays Interact with crystals, same as light, only scale smaller, so
the atoms (electrons) do the interaction.
One of the first X-rays of a body part was done by Röntgen, Whose hand is it?
Röntgen discovered X-rays in 1895.
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Entertainment Value of X-raysUnknown and invisible X-rays can reveal the inside of the body and their bones: such a mystery has given rise to numerous unscientific exhibitions(look for the X-ray source)1888 – 1912…
Taken from:" Crystallography: Past and Present” Hodeau, Guinebretiere Applied Physics 2007, A89, 813-823
Sir William Henry Braggpioneered the determination of crystal structure by X-ray diffraction methods (1915)Clinton J. Davisson (with
George P. Thomson) discovered that electrons can be diffracted like light waves (1937)
X-ray diffraction Nobel Prizes 1901 W. C. Roentgen discovery of x-rays.
1914 M. von Laue x-ray diffraction from crystals.
1915 W. H. Bragg and W. L. Bragg crystal structurederived from x-ray diffraction.
1917 C. G. Barkla radiation of elements.
1924 K. M. G. Siegbahn x-ray spectroscopy.
1927 A. H. Compton scattering of x-rays by electrons.
1936 P. Debye diffraction of x-rays and electrons in gases.
1937 C.J. Davisson and G.P. Thomson diffraction ofx-rays by electrons.
1954 L. Pauling The chemical bond and structures ofcomplex substances.
1962 J. Watson, M. Wilkins, F. Crick structure of DNA.
1962 Max F. Perutz and John C Kendrew structures of globular proteins.
1964 D. Hodgkin structure of important biomolecules.
1976 B. Lipscomb structure of boron hydrides.
1979 A.M. Cormack and G.N. Hounsfield computed axial tomography.
1981 K. M. Siegbahn electron spectroscopy.
1982 A. Klug structures of nucleic acid-protein complexes.
1985 H. Hauptman, J. Karle direct methods.
1987 J. Deisenhofer, R. Huber, M. Michel structural evidence of a photosynthetic reaction center.
1988 J. Deisenhofer, R. Huber, H. Michel Structure of proteins.
1997 B. Brockhouse, C. Shull neutron diffraction
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X-ray diffraction patterns led to the discovery of the DNA double helix, that were predicted by Watson And Crick.
D. Rosalind Franklinin 1951 took first
diffraction patterns anddescribed DNA.
Protein Crystallography
X-ray crystallography of biological molecules took off with Dorothy Crowfoot Hodgkin, who solved the structures of cholesterol (1937), penicillin (1946) and vitamin B12 (1956), for which she was awarded the Nobel Prize in Chemistry in 1964. In 1969, she succeeded in solving the structure of insulin, on which she worked for over thirty years.
Structure of sperm whale myoglobin by Sir John Cowdery Kendrew, for which he shared the Nobel Prize in Chemistry with Max Perutz in 1962.
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Protein Crystallography
Collected an trained what would be some of the great Protein crystallographers and researchers to exist in one location.
THE PROTEIN STRUCTURE PROJECT, 1950-1959: FIRST CONCERTED EFFORT OF A PROTEIN STRUCTURE DETERMINATION IN THE U.S. David Harker
ribonuclease
G.B. Target, Myoglobin and Hemoglobin
Protein Crystallography
Protein X-ray crystallographic studies of blood coagulation proteins in the The lab of Alexander Tulinsky led to the structure determination of human alpha-thrombin, one of the first structures of thrombin that were reported.
PROTEIN STRUCTURES AFTER PSP Project
Labs sprung up to do structures in a small collaborative setting.
A. Tulinsky, MSUBill Lipscomb, HarvardLyle Jensen, University of Washington
Most Of these crystallographers were postdocs of Kendrew and Perutz coming off the triumphant structure determinations of myoglobin and hemoglobin in Great Britain.
OR the PSP.
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Powder X-ray DiffractionThere are many different diffraction techniques that
can answer different questions.
Blakely, Bruno, Poltavets Inorg. Chem. 2011, 50, 6696-6700.
Identification and Purity Check is the main purpose and most widely used of PXRD techniques.
Academic, R&D, Industrial, Manufacturing, Mining, Pharmaceutical to name a select few.
A. BauxiteB. FeldsparC. GypsumD. Lyonsite
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B. Feldspar“The location of the feldspar suggests protracted magmatic activity under the Martian surface could produce large-scale granite deposits, the study team said.”Read more at:
http://www.redorbit.com/news/space/1113006200/mars-has-granite-111813/#VRqwAH1ykfKCdccd.99
Small Molecule Crystallography
Experimental set up used by Friedrich, Knipping & Laue and one of the first Laue pattern. 1912
1913- William Henry Bragg and William Lawrence Bragg solve NaCl.
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Small Molecule Crystallography The determination of the connectivity of the atoms in a
compound and the way the molecule (or molecules) pack to form a solid crystalline material.
Exact connectivity. Bond distances and angles. Complete identification of the compound. Identification of lattice.
Single Crystal Crystal lattice is well defined with small repeating units in three dimensions.
Identification
Lindsey Jamula , James K. McCusker Unpublished results. Montney, Supkowski, Staples, LaDuca J. Solid State Chem.
2009, 182, 8-17.
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Identification Pentadecanuclera Complex or Europium(II)
with Tyrosine
Wang, Zheng, Jin, Staples Angew. Chem. Int. Ed. 1999, 38, 1813-1815.[Eu15(Cl)(mu3-OH)20(mu2-H2O)5(OH)12(H2O)8][ClO4]2 * 56H2O
P3-P1' beta-strand mimetic inhibitors of thrombin
Charles, Matthews, Zhang, Tulinsky, Khan J. Med. Chem, 1999, 42, 1376-1383 .
Vanchura, Preshlock, Roosen, Kallepalli, Staples, Maleczka, Singleton, Smith Chem. Comm. 2010, 46, 7724-7726
Identification of Catalysis
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Chiral Reagents and Active Site Observations
Shiff Base Precursors Mediating Asymmetric Carbenoid Insertion Reactions.
Dakin, Ong, Panek, Staples, Stavropoulos Organometallics 2000, 19, 2896-2908
DiscoveryFirst Electride Synthesize here at MSU.
Dawes, S.B.; Ward, D.L.; Huang, R.H.; Dye, J.L. J. Am.
Chem. Soc. 1986,108, 35341
Cs+( 18C6).e-.
Redko, M.Y.; Jackson, J.E.; Huang, R.H;Dye, J.L.J. Am.Chem. Soc. 2005, 127, 12416
Room Temperature Electride
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X-ray:• must crystallize
• molecules may be large
• better resolution
• structure modified by crystal packing
• oxidation states of metals, etc., may be difficult to determine
•In principle, the structure can be determined in the absence of any additional information
NMR: ( Solution)• must be soluble
• limitations to molecular size
• less accurate
• can capture motion
• spin of the nucleus
• complex structure determination difficult.
OH H
OD D
NN
N
N
O
O
OH
OHH
H
HO OHor
HO
HO
Dissordered OH groups
X-ray Crystallography vs. NMR
NMR: ( Solid State)• Improvements have been made.
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NMR is a Critical Analytical Tool , that is considered to be used in conjunction with X-ray Diffraction.MSU has 10 solution NMR (300-900 MHz) instruments 3 solid State instruments , 3 x-ray instruments.
1H NMR Identification
Regioisomer N. Hewlett, J. Tepe Unpublished results.
Separated via crystallization
NMR data was not helpful in determining which isomer is which. NOE correlations were seen in both cases. (This was not expected in the second case)
Ratio synthesized 5:1
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Solution Versus Solid StateAn NMR and X-ray Story
Typical reaction that was performed in our laboratories, but first time with this particular ligand.
31P NMR should give a single peak
Phosphorus NMR
The product gives a complicated Phosphorus NMR signal, so a 2-D 31P NMR was performed.
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Single Crystal X-ray Structure
Only the second know olefin complex, the first crystallized for Gold(I)
Solution to assignments of solution structure
Solution and solid state are the same.
Dávila, Staples, Fackler Organometallics, 1994, 13, 418-420.
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Chirality
Stereo Chemistry S. Marshall, B. Borhan Unpublished results
Determination of a chiral center is the most important reason in organic chemistry for chemist to use crystallography.
Relative Stereo Chemistry N. Hewlett, J. Tepe Unpublished results.
Polymorphs Very important to industry and Drug Companies The synthesis of polymorphs during drug production and can be
problems in the chemistry or in legal terms.
Fackler, Staples, Khan, Winpenny Acta Cryst. C, 1994, C50, 1020-1023.
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Humidity and channel hydrates in drugs. Anhydrate, Hemihydrate, and Pentahydrate forms Small molecule DPP-IV inhibitor
Kaing, Nagapudi, Liu, Staples, Jona Inter. J. Pharm. 441, 2013 299-306.
Pharmaceutical Applications
Nine fully occupied and one half occupied water molecules in the AMG 222 framework. Therefore, there are 4.75 water molecules per AMG 222 molecule based on the single crystal structure.
Industrial Applications
R-Asparagine Sweet S-Asparagine Bitter
Journal of Modern Medicinal Chemistry, 2013, 1, 10-36.
Inter. J. Pharm. Sci. and Nanotech. , 2009, 4, 309-316.
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Pharmaceutical Applications Chirality Determination One drug good & one bad and FDA.
Penicillamine: S-Penicillamine used to treat arthritis early on Wilson’s disease R- Penicillamine is toxic
S-Penicillamine used to treat arthritis R- Penicillamine is toxic
Polymorphs in Pharmaceuticals
Form I, bioavailability very good, made into capsule and marketed 1996.
1998 form II discovered and its solubility caused the capsule to be removed from the market place.
Chemburkar, S.R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S. et al. (2000) Organic
Process Research & Development 4 (5): 413.
Ritonavir
is an antiretroviral drug, used to treat HIV infection and AIDS
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Solving Physical Properties using X-ray Crystallography
Bonding questions Electrical Conductivity Luminescence
Non-Linear Optical Properties
Polymer Formation
A few examples
Why Study Gold? Gold Drugs found to combat rheumatoid arthritis.
Gold has some good Properties Malleability Conductivity resistance to corrosion Photochemistry
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Photochemistry
Absorption of light by a species A, Leads to the formation of a short-lived excited state molecule A*
A + hυ → A*
Emission can be from a singlet excited state called fluorescencesmall Stokes shift, short lifetimes ( 10 -9 secs)or
Emission can be from a triplet excited state called phosphorescence
large stokes shift, long lifetimes ( > 10 -6 secs)
Photochemistry of Gold (Ph3P)3AuCl - First reports of a luminescent gold(I) complex
Gold (I) complexes also show a short Au---Au interaction in the solid state
Three-coordinate gold(I) complexes
Gold-Sulfur complexes
Z. Dori, Chem. Commun. 1970
General reference: D.M. Roundhill “ Photochemistry and Photophysics of Metal Complexes”, 1994
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Gold Sulfur luminescence
Gold(I) shows a typical Au--Au interaction in the solid state which gives rise to the photochemistry.
Forward, Bohmann, Fackler, Staples Inorg. Chem. 1995, 34, 6330-6336
Need Luminescence in Water
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Synthesis of water soluble luminescent complexes
Emission spectra shows that in solution the three coordinate speciesexists and does luminescence. THIS ENERGY IS NOT SUFFIENT TO QUENCH SINGLET O2
Forward, Staples, Liu, Fackler Acta Cryst. 1997, C53, 195-197 Forward, Bohmann, Fackler, Staples Inorg. Chem. 1995, 34, 6330-6336
Investigation of the chemistry with these ligands have resulted in a number of publications and
interesting structures
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Non-Linear Optical Properties
Electron microscope picture of the solid crystals, notice the ends are brighter than the middle.
This linear chain of atoms allows for easy electrontransfer. This compound oxidizes easily to the metal-metal bonded trimer with many oxidants.
Organometallics, 1987, 6, 1692
Non-Linear optical Properties
Electron microscope shows intense conductivity.Notice the very fine threads of light. The lack ofone area that is lighter than the other!
Although this transfers electrons and has very nice luminesceIt does not transfer electrons down the chain of metals to form metal-metal bonds.
Inorg. Chem. 1989 , 28, 4623 J. Am. Chem. Soc. 1988, 110, 3308
Also unreported results
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Decarboxylation in Polymer Formation
Gold(I) carboxylate complexes were studied to understand their chemistry.
Needed to understand bonding
Allowed the formation of a stable, foamable, gold containing organic carboxlate polymer
Fackler, Khan, King, Staples Organometallic 1991, 10, 2178-2183
Khan, Fackler, Chum, Paquet J. Polymer Sci. 1993, 31, 2353-2364
Helping Theory Provide Answers
MM2 calculations, confirmation starting position Structural explanation and understanding the chemistry Used in Molecule binding Site Studies in all kinds of molecules,
Proteins to simple coordination complexes.
Noble Prize in Chemistry 2013 to theorist, in which “without crystallographic results to compare to Theorist would not have been able to devise such great theories.” M. Karplus
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MM2 Calculations and Conversion Energy
Used to study the conversion energy from one to the other.
Used MM2 calculations as the basis for the energy.
Wang, Doering, Staples J. Chem. Crystallog., 1999, 29, 977-981.
Theory to explain observed geometry
Comparison of three occupied orbitals involved in the Ru=N bond at the optimal and tetrahedrally-constrained structures of Ru(NH)(PH3)3.
The Ru(II) imido has a geometry quite remote from tetrahedral.
A.K. Singh, B.G. Levine, R.J. Staples, A.L. Odom Chem. Comm., 2013, 49, 10799-10801.
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Crystallography Is ARTJournals often use Crystallography results to highlight journal covers.
Journal Covers Created because of interesting chemistry and ART!!.
Where to Next•Ultra-Fast X-ray Diffraction (femtoseconds)•Combining many multiple tiny crystals•High resolution to 1µm to 1 Å•X-ray Tomography ( Imaging)•Laser Induced Reaction X-ray diffraction•Magnetic effects, electron density maps•CRYO-EM•MICRO-ED•Single Molecule X-ray Diffraction.
LLNL scientists created the shortest, purest X-ray laser pulses ever achieved, Billion times brighter than any available.
femtosecond atomic X-ray laser
http://www.photonics.com/Article.aspx?AID=54700
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Transmission Electron Microscope
Molecular Biology of the Cell. 4th edition.
Ingredients to obtain a high-resolution structure by Cryo-EM
Well-behaved sample in thin vitreous ice
Well maintained TEM equipped with a direct
electron detector
Computational resources
Hi-res Structure
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Cryo-EM - Nobel Prize 2017
https://www.nobelprize.org/uploads/2018/06/popular-chemistryprize2017.pdf
STRUCTURE OF BACTERIORHODOPSIN SOLVED BY HENDERSON
Jones et al, ACS Cent. Sci., 2018, 4, 11, 1587-1592
MicroED• Using the electron beam and the microscope to collect
diffraction data• Rapid structure determination of small molecules
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Jones et al, ACS Cent. Sci., 2018, 4, 11, 1587-1592
MicroED• Ability to identify individual compounds from a mixture
Identification of four different compounds from a mixture from a single grid square
MicroED – proteinProtein Year Resolution
Lysozyme(14.4 kDa)
2013 2.9 Å
Lysozyme(14.4 kDa)
2014 2.5 Å
Catalase(245 kDa)
2014 3.2Å
Sup35 prion protein core(905 Da)
2016 1.0 Å
Trypsin(23.4 kDa)
2017 1.7 Å
Xylanase(21.1 kDa)
2017 2.3 Å
Thaumatin(22.2 kDa)
2017 2.5 Å
TGF-b/TbRII complex(22.9 kDa)
2017 2.9 Å
Au146(p-MBA)57 nanoparticle(37.5 kDa)
2017 0.85 Å
Proteinase K(28.9 kDa)
2018 1.7 ÅNannenga et al, eLife 2014;3:e03600Nannenga et al, Nat Methods 16, 369–379 (2019)
Catalase
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Crystals and HealingOne could say that as long as we have existed as a species, we have had an affinity with Crystals and things around us.
Gems were and still are treasure items in society.
Crystal Healing Medicine evolved in the early 1500’s
Still Practiced today.
COURSE SCHEDULE ZOOM Meeting Tuesday, Thursday 12:40-2:00 P.M. NO Spring Break Week, Note 2 days off at different time. I plan to be in most mornings in the Chemistry
Department for questions. Contact me if you need help!!!!!!!!
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Getting Crystal on Fiber or Loop
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