Welcome to CHEM BIO 3OA3! Bio-organic Chemistry [OLD CHEM 3FF3]

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Welcome to CHEM BIO 3OA3!Bio-organic
ChemistryOLD CHEM 3FF3

• Sept. 11, 2009

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• Instructor Paul Harrison
• ABB 418, ext. 27290
• Email pharriso_at_mcmaster.ca
• Course website http//www.elm.mcmaster.ca/
• Lectures MW 0830, F 1030 (ABB/106)
• Office Hours M 1230-230 or by appointment
• Labs
• 230-530 R or F (ABB 217)
• Every week
• Labs start next Fri. Sept. 17, 2009

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Web site update

• ELM page
• Lectures 1 includes everything for today, and
  approx. 1 week of material intro and bases
• Course outline
• Detailed course description lecture-by-lecture
• Calendar

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• For Thursday 11th Friday 12th
• Check-in, meet TA, safety and Lab 1 (Isolation of
  Caffeine from Tea)
• Lab manuals Available on web MUST bring printed
  copy
• BEFORE the lab, read lab manual intro, safety and
  exp. 1
• Also need
• Duplicate lab book (20B3 book is ok)
• Goggles (mandatory)
• Lab coats (recommended)
• No shorts or sandals
• Obey safety rules marks will be deducted for
  poor safety
• Work at own pacesome labs are 2 or 3 wk labs.
  In some cases more than 1 exp. can be worked in a
  lab periodyour TA will provide instruction

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• Evaluation
• Assignments 2 x 5 10
• Labs -write up 15
• - practical mark 5
• Midterm 20
• Final 50
• Midterm test
• Fri. Oct. 30, 2009 at 700 pm
• Assignments Oct. 9 Oct. 19
• Nov. 13 Nov. 23
• Note academic dishonesty statement on outline-NO
  copying on assignments or labs (exception when
  sharing results)

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• Texts
• Dobson Foundations of Chemical Biology,
  (Optional- bookstore)
• Background Refreshers
• An organic chemistry textbook (e.g. Solomons)
• A biochemistry textbook (e.g. Garrett)
• 2OA3/2OB3 old exam on web
• This course has selected examples from a variety
  of sources, including Dobson
• Buckberry Essentials of Biological Chemistry
• Dugas, H. "Bio-organic Chemistry"
• Waldman, H. Janning, P. Chemical Biology
• Also see my slides on the website

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• What is bio-organic chemistry? Biological chem?
  Chemical bio?
• Chemical Biology
• Development use of chemistry techniques for
  the study of biological phenomena (Stuart
  Schreiber)
• Biological Chemistry
• Understanding how biological processes are
  controlled by underlying chemical principles
  (Buckberry Teasdale)
• Bio-organic Chemistry
• Application of the tools of chemistry to the
  understanding of biochemical processes (Dugas)
• Whats the difference between these???
• Deal with interface of biology chemistry

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Simple organics eg HCN, H2CO (mono-functional) C
f 20A3/B3
BIOLOGY
CHEMISTRY
Life large macromolecules cellscontain 100,
000 different compounds interacting
Biologically relevant organics polyfunctional
1 Metabolism present in all cells (focus of
3OA3) 2 Metabolism specific species, eg.
Caffeine (focus of 4DD3)
How different are they?
CHEMISTRY Round-bottom flask
BIOLOGY cell
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• Exchange of ideas
• Biology Chemistry
• Chemistry
• Explains events of biology mechanisms,
  rationalization
• Biology
• Provides challenges to chemistry synthesis,
  structure determination
• Inspires chemists biomimetics ? improved
  chemistry by understanding of biology (e.g.
  enzymes)

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Key Processes of 1 Metabolism

• Bases sugars ? nucleosides
  nucleic acids
• Sugars (monosaccharides)
  polysaccharides
• Amino acids
  proteins
• Polymerization reactions cell also needs the
  reverse process
• We will look at each of these processes, forwards
  and backwards, in 4 parts, comparing and
  contrasting the reactions
• How do chemists synthesize these structures?
• How might these structures have formed in the
  pre-biotic world, and have led to life on earth?
• How are they made in vivo?
• Can we design improved chemistry by understanding
  the biology biomimetic synthesis?

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Properties of Biological Molecules that Inspire
Chemists

• Large ? challenges for synthesis
• for structural prediction (e.g. protein
  folding)
• 2) Size ? multiple FGs (active site) ALIGNED to
  achieve a goal
• (e.g. enzyme active site, bases in NAs)
• 3) Multiple non-covalent weak interactions ? sum
  to strong, stable binding non-covalent complexes
• (e.g. substrate, inhibitor, DNA)
• 4) Specificity ? specific interactions between 2
  molecules in an ensemble within the cell

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• 5) Regulated ? switchable, allows control of cell
  ? activation/inhibition
• 6) Catalysis ? groups work in concert
• 7) Replication ? turnover
• e.g. an enzyme has many turnovers, nucleic
  acids replicate

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Evolution of Life

• Life did not suddenly crop up in its current form
  of complex structures (DNA, proteins) in one
  sudden reaction from mono-functional simple
  molecules
• In this course, we
• will follow some of the
• ideas of how life may
• have evolved

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RNA World

• Catalysis by ribozymes occurred before protein
  catalysis
• Explains current central dogma
• Which came first nucleic acids or protein?
• RNA world hypothesis suggests RNA was first
  molecule to act as both template catalyst
• catalysis replication

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• How did these reactions occur in the pre-RNA
  world? In the RNA world? in modern organisms?
• CATALYSIS SPECIFICITY
• How are these achieved? (Role of NON-COVALENT
  forces BINDING)
• a) in chemical synthesis
• b) in the pre-biotic world
• c) in vivo how is the cell CONTROLLED?
• d) in chemical models can we design better
  chemistry through understanding biochemical
  mechanisms?

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Relevance of Labs to the Course

• Labs illustrate
• Biologically relevant small molecules (e.g.
  caffeine Exp 1, related to bases)
• Cofactor chemistry pyridinium ions (e.g. NADH,
  Exp 2 4)
• Biomimetic chemistry (e.g. simplified model of
  NADH, Exp 2)
• Chemical mechanisms relevant to catalysis (e.g.
  NADH, Exp 2)
• Structural principles characterization (e.g.
  sugars anomers of glucose, anomeric effect,
  diastereomers, NMR, Exp 3)

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• Application of biology to stereoselective
  chemical synthesis (e.g. yeast, Exp 4)
• Synthesis of small molecules (e.g. peptides,
  drugs, dilantin, esters, Exp 5,6,7)
• Chemical catalysis (e.g. protection activation
  strategies relevant to peptide synthesis in vivo
  and in vitro, Exp 5)
• Comparison of organic and biological reactions
  (Exp. 6)
• Enzyme mechanisms and active sites (Exp. 7)
• All of these demonstrate inter-disciplinary area
  between chemistry biology

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• Two Views of DNA
• Biochemists view shows overall shape,
  ignores atoms bonds
• Chemists view atom-by-atom structure,
  functional groups illustrates concepts from
  2OA3/2OB3
• GOAL to think as both a chemist and a
  biochemist i.e. a chemical biologist!

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Biochemists View of the DNA Double Helix
Minor groove
Major groove
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Chemists View
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BASES

• Aromatic structures
• all sp2 hybridized atoms (6 p orbitals, 6 p e-)
• planar (like benzene)
• N has lone pair in both pyridine pyrrole ?
  basic (H acceptor or e- donor)

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6 p electrons, stable cation ? weaker acid,
higher pKa ( 5) strong conj. base
sp3 hybridized N, NOT aromatic ? strong acid, low
pKa ( -4) weak conj. base

• Pyrrole uses lone pair in aromatic sextet ?
  protonation means loss of aromaticity
  (BAD!)
• Pyridines N has free lone pair to accept H
• ? pyridine is often used as a base in organic
  chemistry, since it is soluble in many common
  organic solvents

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• The lone pair also makes pyridine a H-bond
  acceptor e.g. benzene is insoluble in H2O but
  pyridine is soluble
• This is a NON-specific interaction, i.e., any
  H-bond donor will work

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What about pyrrole?

• Is it soluble in water?

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Other groups form H-bonds

• Electronegative atoms, e.g. carbonyl group
• Acetone is soluble in water, but propane is not
• Again, non-specific interactions

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Bifunctional compounds
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Bifunctional compounds
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Contrast with Nucleic Acid Bases (A, T, C, G, U)
Specific!

• Evidence for specificity?
• Why are these interactions specific? e.g. G-C
  A-T

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• Evidence?
• If mix G C together ? exothermic reaction
  occurs change in 1H chemical shift in NMR other
  changes ? reaction occurring
• Also occurs with A T
• Other combinations ? no change!

e.g. Guanine-Cytosine

• Why?
• In G-C duplex, 3 complementary H-bonds can form
  donors acceptors molecular recognition

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• Can use NMR to do a titration curve
• Favorable reaction because ?H for complex
  formation -3 x H-bond energy
• ?S is unfavorable ? complex is organized ?
  3 H-bonds overcome the entropy of complex
  formation
• Note In synthetic DNAs other interactions can
  occur

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• Molecular recognition not limited to natural
  bases

Forms supramolecular structure 6 molecules in a
ring
? Create new architecture by thinking about
biology i.e., biologically inspired chemistry!
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Synthesis of the Bases in Nucleic Acids

• Thousands of methods in heterocyclic chemistry
  well do 1 example
• Juan Or (1961)
• May be the first step in the origin of life
• Interesting because H-CN/CN- is probably the
  simplest molecule that can be both a nucleophile
  electrophile, and also form C-C bonds

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Mechanism?
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Other Bases?
All these species are found in interstellar
space observed by e.g. absorption of IR
radiation a natural example of IR
spectroscopy! Try these mechanisms!
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Properties of Pyridine

• Weve seen it as an acid an H-bond acceptor
• Lone pair can act as a nucleophile

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• Balance between aromaticity charged vs
  non-aromatic neutral!
• ? can undergo REDOX reaction reversibly

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• Interestingly, nicotinamide may have been present
  in the pre-biotic world
• NAD or related structure may have controlled
  redox chemistry long before enzymes involved!

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Another example of N-Alkylation of Pyridines
This is an SN2 reaction stereospecific with
INVERSION
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References

• Solomons
• Amines basicity ch.20
• Pyridine pyrrole pp 644-5
• NAD/NADH pp 645-6, 537-8, 544-6
• Bases in nucleic acids ch. 25
• Also see Dobson, ch.9
• Topics in Current Chemistry, v 259, p 29-68

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