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A personalview byLajosKOVÁCSUniversity ofSzegedHungary
A minimalist introduction to(bio)organic chemistry
TRIoH SymposiumFrankfurtMarch 23, 2005
Part 1: Basic conceptsPart 2: How does a chemist work?
How many compounds are known to date?
Substances registered in the Registry Database ofChemical Abstracts (1907-2005)
81,427,420 registeredorganic and inorganicsubstances andsequences(March 5, 2005)
person-years to draw one structure per minute
Structure(s)
PropertiesFunction(s)
Can you imagine akiss without lips?
Structures: the basic language of chemistry
an organic compound consists of a backbone (a relativelyunreactive, apolar carbon skeleton and the necessary
number of hydrogens) and the functional group(s)
Functional groups: polar atom or atom groups within a molecule that displaya characteristic combination of chemical and physical properties, e.g.:
alkenes
aromaticcompounds(arenes)
alcohols
amines(primary)
carboxylicacids
amides
Structures: dialects of a language
empirical formulas - 2D structural formulas - 3D structural formulas
Backbones and functional groups
the ensemble of functional groups and backbonedetermines the fundamental physical and chemical
properties of (organic) compounds e.g.
P aggregation state
P colour
P chemical reactivity
P acid-base character
Melting and crystallization: fats and oils
P natural fats are mixtures and
P crystallise in polymorphic forms
C16
C18
C18
average chain length (carbonatoms)
average number of doublebonds (per fatty acid residue)
lard
cocabutter
oliveoil
herringoil
cow’smilk fat
humanmilk fat
Melting and crystallization: the secrects ofa fine chocolate
increasing order
Crystal packing in triglycerides
33.8 C($-3)
A good chocolate melts in yourmouth but not in your hands...
Colour: beta-carotene
Chemical reactivity: determined mainly bythe functional groups
the distinction offunctional groups andbackbones issomewhat arbitrary
BUT...
Acid/base character: a key concept 1.
GMP
coloured groups involvedin protonation ordeprotonation
-logK = pK-log[H+] = pH0 < pH < 14
if [A- ]=[HA]then K = [H+]and pK = pH
Acid/base character: a key concept 2.
3.70
9.08
logD = lipophilicity(logP) in the functionof pH
lipid-soluble
water-soluble
Trifluoperazine (Stelazine)antianxiety, antiemetic,
antipsychotic drug
The shape of molecules: constitution
Hexane isomers (C6H14):
The shape of molecules: configuration
D-leucinesweet
L-leucineslightly bitter
When configuration matters: vision
The shape of the molecules: conformation
Fibroblast Growth Factor (FGF) acidic 1(102- 111, decapeptide, from bovine brain)
H-HisAlaGluLysHisTrpPheValGlyLeu-OH
An arbitrary conformation(solvent-accessible surfaceshown)
Crystal structure of the tyrosine kinase domain of fibroblast growth factorreceptor 1 in complex with su4984 inhibitor
"-helix$-turn
random coil
inhibitorcomplexed
The Holy Trinity
Structure(s)
PropertiesFunction(s)
P constitution
P configuration
P conformation
P aggregation state
P solubility
P elasticity
P colour
P chemical reactivity
P acidity/basicity etc.
P structural materials
P energy storage forms
P enzymes
P drugs
P fuels
P electronics etc.
Part 1: Basic conceptsPart 2: How does a chemist work?
Do I need to know this at all???
If you can manage alone...
...or in company
Areas of chemistry
P theoretical
P physical
P inorganic
P organic
P applied
P analytical
P structural
P environmental
P macromolecularetc.
P theoretical
P experimental
< synthetic (preparative)
< analytical
An iterative cycle
Synthesis design
Ppreparation of carbon framework and/or
P functional group manipulations(addition/interconversion/removal)
Pbuilding blocks< e.g. CambridgeSoft’s ChemACX Database:
690,463 commercially available products
A synthetic plan of Sildenafil (ViagraTM)
Tangram puzzles
The synthesis of Sildenafil (ViagraTM)
Purification: getting the right stuff
Pcrystallisation (crystalline substances)
Pdistillation (liquids)
Pchromatography (for the rest)< layer/column< atmospheric/forced flow< analytical/preparative
Structural elucidation: solving the puzzle
You need a propertool...
The tools
Pultraviolet spectroscopy (UV): unsaturated bonds(marginal role)
P infrared spectroscopy (IR): presence/absence offunctional groups
Pnuclear magnetic resonance (NMR): carbon/proton etc.framework (13C, 1H ...), fine structure (configuration,conformation)
Pmass spectrometry (MS): molecular weight,fragmentation
PX-ray: framework of heavy atoms in solid state(configuration, conformation)
Instruments, instruments...
How much time does this take?(Optimistic estimates)
days to weeks
days to weeksper step
days to weeksper step
days to weeksper step
days toweeks
percompound
but...
P availability ofbuilding blocks
P stereoisomers
P scaling-up problems
P reproducibility
P multistep syntheses
P yields
P timing etc.
...the preparation of a new compound in reasonable amount in amultistep synthesis involving new reaction(s) may easily take a year!
Just too slow?
but...
P for delicate objectsyou need chisels nota chain-saw
Speeding up the synthesis
(An arbitrary selection of currently available methods)
Psolid phase synthesis< oligomers (peptides, nucleotides), small molecules
Pcombinatorial and parallel synthesis< lead optimisation
Pmulticomponent reactions< shortening reaction pathways
Pmicrowave activation< accelerating reactions
Pmetathesis reactions< synthesising complex frameworks etc.
Solid phase synthesis of Sildenafil (ViagraTM)
but... P complicated reagents
P small-scale synthesis
Biginelli reaction
conventionalheating
microwaveheating
but...P you need a suitable reaction to speed up...
Multicomponent reactions & microwave activation
Accelerating the purification 1.UPLC (Ultra Performance Liquid Chromatography, Waters)X-LC (Extreme High Pressure Liquid Chromatography, Jasco)
particle size (:m)
pressure applied (bar)
HPLC UPLC
5-10 < 2
400 1,000-7,500
UPLC (right) separates many more components outof urine samples than does conventional HPLC (left)
A prototype UPLCinstrument
but you needsome cash...
Accelerating the purification 2.OPLC (Overpressurised Layer Chromatography/Optimum Performance Laminar Chromatography, OPLC-NIT/Bionisis)
P forced-flow (50 bar) planar chromatography (acombination of TLC and HPLC)
P simultaneous multi-sample processing (up to 70)
P fast separation (av. 10 to 20 min)
P low solvent consumption (< 5mL/run)
P analytical and preparative (0.2-20 mg)
separation of xanthines(caffeine, theophylline,theobromine) in tea
but you needsome cash...
Picture credits 1.P blacksmith shop: http://www.anvilfire.com/home/images/slideshow/g_fahrenwald/blacksmith_shop_1.htm
P iceberg: http://en.wikipedia.org/wiki/Image:Iceberg.jpg
P lips and mouths:< http://www.portrait-artist.org/ basics/shading.html< http://www.kristoffer.com/temp/Lips.jpg< http://drake.marin.k12.ca.us/students/jollyn/portfolio/sketcheshtm.htm< http://www.africa.upenn.edu/faminefood/images/Hankalta%20eating%20fruit.jpg< http://www.public.asu.edu/~atjlb/FOOT%20IN%20MOUTH.JPG< http://world.std.com/~damned/Wendy/Pix/kiss.jpg
P bones: http://www.arch.soton.ac.uk/Research/CAAA/bones/pompeii2.htm
P dog skeleton: http://www.wolfshadow.co.uk/Dog%20skeleton.jpg (edited)
P figures on fats and oils:< T. P. Coultate: Food. The chemistry of its components. Royal Society of Chemistry, Cambridge, 2002, p. 104-
109.< http://www.public.asu.edu/~mmcbeath/mcbeath.links/links.html
P beta-carotene UV spectrum: http://omlc.ogi.edu/spectra/PhotochemCAD/html/beta-carotene.html
P colour spectrum: http://www.city.ac.uk/colourgroup/spectrum.gif
P pK and logD predictions: http://www.chemaxon.com/marvin/sketch/demo.html
P amino acid enantiomers: http://web99.arc.nasa.gov/~astrochm/aachiral.html
P FGF inhibitor complex: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1AGW
Picture credits 2.P bikes:< http://www.intellectualpoison.com/Pics/invertedunicycle.jpg< http://www.spicyjoke.com/unicycle.html< http://www.sneltweewielers.nl< http://www.kitepower.com/welcome.html
P tangrams: http://www.bilet.go.ro/origami/origami9.htm
P instruments:< http://www.laserglass.com.cn/measuring%20Instrument.htm< http://www.varianinc.com/image/vimage/docs/corp/businesses/nmr/shared/probe.jpg< http://ncbr.chemi.muni.cz/PICTURES/EQUIPMENT/500MHz.jpg< http://en.wikipedia.org/wiki/Image:Pacific_Northwest_National_Laboratory_800_MHz_NMR_Spectr
ometer.jpg< http://www.physics.utoronto.ca/ ~isotrace/specv01.htm
P wooden statue: http://www.godstatues.com/ wooden-statues-antique.html
P chisels: http://www.woodworking-tool-store.com
P black and white pictures on logging and cameras by Darius Kinsey (1869-1945), e.g.:http://content.lib.washington.edu
P temperature profile of microwave heating: Angew. Chem. Internatl. Ed. Engl. 43, 6250-6284 (2004)
P UPLC: http://pubs.acs.org/isubscribe/journals/cen/82/i47/ html/8247sci3.html?emFrom=emLogin
P OPLC chromatogram: courtesy of Dr. E. Mincsovics (OPLC-NIT Ltd, Budapest)
P cash sack: http://sidereus.org/MONEY/money_dollar_cash-2.htm