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Welcome to CHEM BIO 3OA3!
Bio-organic Chemistry
[OLD CHEM 3FF3]
Sept. 11, 2009
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• Instructor: Paul Harrison
– ABB 418, ext. 27290
– Email: [email protected]
– Course website: http://www.elm.mcmaster.ca/
Lectures: MW 08:30, F 10:30 (ABB/106)
– Office Hours: M 12:30-2:30 or by appointment
– Labs:
2:30-5:30 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-bylecture
• Calendar
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.
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• 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 pace—some labs are 2 or 3 wk labs. In some cases
more than 1 exp. can be worked in a lab period—your TA will
provide instruction
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Evaluation
Assignments
Labs:
2 x 5%
-write up
- practical mark
Midterm
Final
Midterm test:
Fri. Oct. 30, 2009 at 7:00 pm
10%
15%
5%
20%
50%
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,” (Optionalbookstore)
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)
What’s the difference between these???
Deal with interface of biology & chemistry
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Simple organics
BIOLOGY
Life
large macromolecules;
cells—contain ~ 100,
000 different
compounds interacting
CHEMISTRY
eg HCN, H2C=O
(mono-functional)
Biologically relevant organics:
polyfunctional
1 ° Metabolism – present in all cells
Cf 20A3/B3
(focus of 3OA3)
2 ° Metabolism – specific species, eg. Caffeine (focus of 4DD3)
How different
are they?
BIOLOGY:
CHEMISTRY:
cell
Round-bottom flask
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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:
1) How do chemists synthesize these structures?
2) How might these structures have formed in the pre-biotic
world, and have led to life on earth?
3) How are they made in vivo?
4) Can we design improved chemistry by understanding the
biology: biomimetic synthesis?
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Properties of Biological Molecules that Inspire
Chemists
1)
Large → challenges:
for synthesis
for structural prediction (e.g. protein folding)
2)
Size → multiple FG’s (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 monofunctional simple molecules
• In this course, we
HCN + NH3
bases
will follow some of the
nucleosides
ideas of how life may
H2C=O
sugars
phosphate
have evolved:
"pre-RNA world"
more RNA, other
molecules
nucleotides
catalysis
RNA
"RNA world"
CH4, NH3
H2O
amino
acids
"pre-protein world"
RNA
(ribozyme)
peptides
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RNA World
• Catalysis by ribozymes occurred before protein catalysis
• Explains current central dogma:
transcription
translation
protein
RNA
DNA
requires
protein
requires RNA
+ protein
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:
1)
2)
3)
4)
5)
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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6)
Application of biology to stereoselective chemical
synthesis (e.g. yeast, Exp 4)
7) Synthesis of small molecules (e.g. peptides, drugs,
dilantin, esters, Exp 5,6,7)
8) Chemical catalysis (e.g. protection & activation
strategies relevant to peptide synthesis in vivo and in
vitro, Exp 5)
9) Comparison of organic and biological reactions (Exp.
6)
10) 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
1)
Biochemist’s view:
shows overall shape, ignores atoms & bonds
2)
Chemist’s 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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Biochemist’s View of the DNA Double Helix
Minor
groove
Major
groove
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Chemist’s View
O
alkene
O
O P O
O H
H
diastereotopic
Ring
conformation
ax/eq
H
H-bonds
NH
N
O
H
 OH
resonance
O
 bonds
H
H
OH
chirality
2o alcohol
(FG's)
nucleophilic
O +
substitution rxn
O P O
O electrophilic
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BASES
N
H
N
pyridine
pyrrole
• Aromatic structures:
– all sp2 hybridized atoms (6 p orbitals, 6 π e-)
– planar (like benzene)
• N has lone pair in both pyridine & pyrrole  basic (H+
acceptor or e- donor)
ArN:
H+
ArNH+
pKa?
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+
N H
6 π electrons, stable cation  weaker
acid, higher pKa (~ 5) & strong conj.
base
+ H
N
H
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!)
• Pyridine’s 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:
N :
e- donor
base
H-bond
acceptor
O
H
H
e- acceptor
acid
H-bond
donor
• 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?
Other groups form H-bonds
• Electronegative atoms, e.g. carbonyl group:
• Acetone is soluble in water, but propane is not:
..
..
O
• Again, non-specific interactions
O
H
O
H
Bifunctional compounds
N
mp -42oC
bp 115oC
O
mp -47oC
bp 155oC
mp 105-107oC
bp 280-281oC
N
OH
N
H
O
Bifunctional compounds
N
H
O
O
H
N
Contrast with Nucleic Acid Bases
(A, T, C, G, U) – Specific!
Pyrimidines (like pyridine):
O
NH2
NH
N
H
H
*
NH
O
N
O
N
O
N
*
H *
Uracil (U)
(RNA only)
Thymine (T)
(DNA only)
Cytosine (C)
Purines
O
NH2
N
N
N
N
H*
Adenine (A)
O
N
NH
N
H
*
N
NH2
Guanine (G)
* link to sugar
• 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:
H
H
N
O
N
N
H
N
N
N
NH
H
O
N
H
2 lone pairs in
plane at 120o to
C=O bond
H
• Why?
G
C
– 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:
G+C
Ka
GC
get equilibrium constant,
G = -RT ln K = H-TS
• Favorable reaction because ΔH for complex formation =
-3 x H-bond energy
• ΔS 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– we’ll
do 1 example:
– Juan Or (1961)
– May be the first step in the origin of life…
NH2
N
NH3
+
N
HCN
N
H
N
Adenine
Polymerization of HCN
– 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?
H
+
N C
H
H
N
+
H
HN
H
C N
H
N
N
N
H
N
NH
+
H
H
NH3
N
N
H
H
H
H
N
NH
NH2
H
N
tautomerization
N
H
N
N
H
N
N
NH
N
H
NH
+
NH2
N
H
+
NH
N
N
H
N
+
NH2
N
H
N
H
N
N
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Other Bases?
HC N
G, U, T and C
NH3
N
N
N (cyanogen)
H (cyanoacetylene)
** 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
• We’ve seen it as an acid & an H-bond acceptor
• Lone pair can act as a nucleophile:
O
O
N
N
+
+
+
N
X
SN2
R X
+
N R
e.g. exp 2: benzyl dihydronicotinamide: R = PhCH2
O
O
H2N
(like NaBH4)
N
+
aromatic, but
+ve charge
+
Ph
O
"H-"
H2N
N
Ph
electron acceptor:
electrophile
reduction
[O]
oxidation
H2N
H
H
N
non-aromatic,
but neutral
Ph
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• Balance between aromaticity & charged vs non-aromatic
& neutral!
•  can undergo REDOX reaction reversibly:
NAD-H
NAD+ + "H-"
reductant
oxidant
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• Interestingly, nicotinamide may have been present in the
pre-biotic world:
CN
CN
DielsAlder
NH
N
H
electrical
discharge
[O],
hydrolysis of CN
CH4 + N2 + H2
O
NH2
N
1% yield
• NAD or related structure may have controlled redox
chemistry long before enzymes involved!
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Another example of N-Alkylation of Pyridines
Caffeine
O
N
HN
O
O
N
H3 C
N
H
O
N
N
N
N
CH3
CH3
This is an SN2 reaction: stereospecific with INVERSION
R
NH
R
R
Ad
+
+
H3C
S
N
Met
R
CH3
+
Ad
S
Met
S-adenosyl-methionine
(SAM, important co-factor)
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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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