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Welcome to 3FF3! Bio-organic Chemistry

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planar (like benzene) N has lone pair in both pyridine & pyrrole basic (H acceptor or e- donor) ... a H-bond acceptor e.g. benzene is insoluble in H2O but ... – PowerPoint PPT presentation

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Title: Welcome to 3FF3! Bio-organic Chemistry


1
Welcome to 3FF3!Bio-organic Chemistry
  • Jan. 7, 2008

2
  • Instructor Adrienne Pedrech
  • ABB 417
  • Email adriennepedrech_at_hotmail.com
  • -Course website http//www.chemistry.mcmaster.ca/
    courses/3f03/index.html
  • Lectures MW 830 F 1030 (CNH/B107)
  • Office Hours T 1000-1230 F 100-230 or by
    appointment
  • Labs
  • 230-530 M (ABB 302,306) Note course
    timetable says ABB217 230-530 F (ABB 306)
  • Every week except reading week (Feb. 18-22)
    Good Friday (Mar. 21)
  • Labs start Jan. 7, 2008 (TODAY!)

3
  • For Monday 7th Friday 11th
  • Check-in, meet TA, safety and Lab 1 (Isolation of
    Caffeine from Tea)
  • Lab manuals Buy today!
  • 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

4
  • Evaluation
  • Assignments 2 x 5 10
  • Labs -write up 15
  • - practical mark 5
  • Midterm 20
  • Final 50
  • Midterm test
  • Fri. Feb. 29, 2008 at 700 pm
  • Make-up test TBD
  • Assignments Feb.6 Feb.13
  • Mar.7 Mar.14
  • Note academic dishonesty statement on outline-NO
    copying on assignments or labs (exception when
    sharing results)

5
  • 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 notes on the website

6
  • 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

7
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 cell (focus of
3FF3) 2 Metabolism specific species, eg.
Caffeine (focus of 4DD3)
How different are they?
CHEMISTRY Round-bottom flask
BIOLOGY cell
8
  • 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)

9
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 3 parts
  • How do chemists synthesize these structures?
  • How are they made in vivo?
  • Improved chemistry through understanding the
    biology biomimetic synthesis

10
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

11
  • 5) Regulated ? switchable, allows control of cell
    ? activation/inhibiton
  • 6) Catalysis ? groups work in concert
  • 7) Replication ? turnover
  • e.g. an enzyme has many turnovers, nucleic
    acids replicates

12
Evolution of Life
  • Life did not suddenly crop up in its element 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

13
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

14
  • 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 vivo how is the cell CONTROLLED?
  • c) in chemical models can we design better
    chemistry through understanding biochemical
    mechanisms?

15
Relevance of Labs to the Course
  • Labs illustrate
  • Biologically relevant small molecules (e.g.
    caffeine Exp 1)
  • Structural principles characterization (e.g.
    anomers of glucose, anomeric effect,
    diastereomers, NMR, Exp 2)
  • Cofactor chemistry pyridinium ions (e.g. NADH,
    Exp 3 4)
  • Biomimetic chemistry (e.g. simplified model of
    NADH, Exp 3)
  • Chemical mechanisms relevant to catalysis (e.g.
    NADH, Exp 3)

16
  • Application of biology to stereoselective
    chemical synthesis (e.g. yeast, Exp 4)
  • Synthesis of small molecules (e.g. drugs,
    dilantin, tylenol, Exp 5,7)
  • Chemical catalysis (e.g. protection activation
    strategies relevant to peptide synthesis in vivo
    and in vitro, Exp 6)
  • All of these demonstrate inter-disciplinary area
    between chemistry biology

17
  • 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

18
Biochemists View of the DNA Double Helix
Minor groove
Major groove
19
Chemists View
20
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)

21
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

22
  • 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 suffice

23
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

24
  • 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

25
  • 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

26
  • 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!
27
Synthesis of Bases (Nucleic)
  • Thousands of methods in heterocyclic chemistry
    well do 1 example
  • 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

28
Mechanism?
29
Other Bases?
Try these mechanisms!
30
Properties of Pyridine
  • Weve seen it as an acid an H-bond acceptor
  • Lone pair can act as a nucleophile

31
  • Balance between aromaticity charged vs
    non-aromatic neutral!
  • ? can undergo REDOX reaction reversibly

32
  • Interestingly, nicotinamide may have been present
    in the pre-biotic world
  • NAD or related structure may have controlled
    redox chemistry long before enzymes involved!

33
Another example of N-Alkylation of Pyridines
This is an SN2 reaction with stereospecificity
34
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

35
Sugar Chemistry Glycobiology
  • In Solomons, ch.22 (pp 1073-1084, 1095-1100)
  • Sugars are poly-hydroxy aldehydes or ketones
  • Examples of simple sugars that may have existed
    in the pre-biotic world

36
  • Most sugars, i.e., glyceraldehyde are chiral sp3
    hybridized C with 4 different substituents
  • The last structure is the Fischer projection
  • CHO at the top
  • Carbon chain runs downward
  • Bonds that are vertical point down from chiral
    centre
  • Bonds that are horizontal point up
  • H is not shown line to LHS is not a methyl group

37
  • In (R) glyceraldehyde, H is to the left, OH to
    the right ? D configuration if OH is on the
    left, then it is L
  • D/L does NOT correlate with R/S
  • Most naturally occurring sugars are D, e.g.
    D-glucose
  • (R)-glyceraldehyde is optically active rotates
    plane polarized light (def. of chirality)
  • (R)-D-glyceraldehyde rotates clockwise, ? it is
    the () enantiomer, and also d-, dextro-rotatory
    (rotates to the right-dexter)
  • ? (R)-D-()-d-glyceraldehyde
  • its enantiomer is (S)-L-(-)-l-glyderald
    ehyde
  • ()/d (-)/l do NOT correlate

38
  • Glyceraldehyde is an aldo-triose (3 carbons)
  • Tetroses ? 4 Cs have 2 chiral centres
  • 4 stereoisomers
  • D/L erythrose pair of enantiomers
  • D/L threose - pair of enantiomers
  • Erythrose threose are diastereomers
    stereoisomers that are NOT enantiomers
  • D-threose D-erythrose
  • D refers to the chiral centre furthest down the
    chain (penultimate carbon)
  • Both are (-) even though glyceraldehyde is () ?
    they differ in stereochemistry at top chiral
    centre
  • Pentoses D-ribose in DNA
  • Hexoses D-glucose (most common sugar)

39
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40
Reactions of Sugars
  • The aldehyde group
  • Aldehydes can be oxidized
  • reducing sugars those that have a free
    aldehyde (most aldehydes) give a positive
    Tollens test (silver mirror)
  • Aldehydes can be reduced

41
  • Reaction with a Nucleophile
  • Combination of these ideas ? Killiani-Fischer
    synthesis used by Fischer to correate
    D/L-glyceraldehyde with threose/erythrose
    configurations

42
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43
Reactions (of aldehydes) with Internal
Nucleophiles
  • Glucose forms 6-membered ring b/c all
    substituents are equatorial, thus avoiding
    1,3-diaxial interactions

44
  • Can also get furanoses, e.g., ribose
  • Ribose prefers 5-membered ring (as opposed to
    6) otherwise there would be an axial OH in the
    6-membered ring

45
  • Why do we get cyclic acetals of sugars? (Glucose
    in open form is ltlt 1)
  • Rearrangement reaction we exchange a CO bond
    for a stronger C-O s bond ? ?H is favored
  • There is little ring strain in 5- or 6- membered
    rings
  • ?S there is some loss of rotational entropy in
    making a ring, but less than in an intermolecular
    reaction1 in, 1 out.

significant ve ?S! ??G ?H -
T?S
Favored for hemiacetal
Not too bad for cyclic acetal
46
Anomers
  • Generate a new chiral centre during hemiacetal
    formation (see overhead)
  • These are called ANOMERS
  • ß-OH up
  • a-OH down
  • Stereoisomers at C1 ?diastereomers
  • a- and ß- anomers of glucose can be crystallized
    in both pure forms
  • In solution, MUTAROTATION occurs

47
Mutatrotation
48
In solution, with acid present (catalytic), get
MUTAROTATION not via the aldehyde, but oxonium
ion
  • At equilibrium, 3862 aß despite a having an
    AXIAL OHWHY? ANOMERIC EFFECT

49
Anomeric Effect
oxonium ion
O lone pair is antiperiplanar to C-O s bond ?
GOOD orbital overlap (not the case with the
ß-anomer)
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