welcome to chem bio 3oa3! bio-organic chemistry [old chem 3ff3]
DESCRIPTION
Welcome to CHEM BIO 3OA3! Bio-organic Chemistry [OLD CHEM 3FF3]. Sept. 11, 2009. 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 - PowerPoint PPT PresentationTRANSCRIPT
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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
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 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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EvaluationAssignments 2 x 5% 10%
Labs: -write up 15% - practical mark 5%
Midterm 20%Final 50%
Midterm test:
Fri. Oct. 30, 2009 at 7:00 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)
What’s the difference between these???
Deal with interface of biology & chemistry
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BIOLOGY CHEMISTRY
Simple organics
eg HCN, H2C=O
(mono-functional)
Cf 20A3/B3Biologically relevant organics: polyfunctional
Life
large macromolecules; cells—contain ~ 100, 000 different compounds interacting
1 ° Metabolism – present in all cells (focus of 3OA3)
2 ° Metabolism – specific species, eg. Caffeine (focus of 4DD3)
CHEMISTRY:
Round-bottom flask
BIOLOGY:
cell
How different are they?
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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° MetabolismBases + 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 synthesisfor 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 mono-functional simple molecules• In this course, we
will follow some of the
ideas of how life may
have evolved:
HCN + NH3 bases
H2C=O sugars
nucleosides
phosphate
nucleotides
RNA
"RNA world"
catalysismore RNA, other molecules
CH4, NH3
H2Oamino acids
peptidesRNA
(ribozyme)
"pre-RNA world"
"pre-protein world"
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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
DNA
transcriptionRNA protein
translation
requiresprotein
requires RNA+ protein
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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 CourseLabs illustrate:
1) Biologically relevant small molecules (e.g. caffeine –Exp 1, related to bases)
2) Cofactor chemistry – pyridinium ions (e.g. NADH, Exp 2 & 4)
3) Biomimetic chemistry (e.g. simplified model of NADH, Exp 2)
4) Chemical mechanisms relevant to catalysis (e.g. NADH, Exp 2)
5) 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-atomstructure, 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
Major groove
Minor groove
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N
NH
O
O
O
H
OH
H
OH
HH
OP OOO
HH
OP
O
OO
2o alcohol(FG's)
alkene
bonds
resonance
Ringconformationax/eq
H-bonds
nucleophilic
electrophilic
substitution rxn
chirality
+
diastereotopic
Chemist’s View
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BASES
N NH
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
N
H
H
+
+
6 π 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!)
• 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:
• This is a NON-specific interaction, i.e., any H-bond donor will work
N HO
H:
e- donor e- acceptor
H-bond acceptor
H-bonddonor
acidbase
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:
• Again, non-specific interactions
O OH
OH.. ..
Bifunctional compounds
N OH NH
O
N O
mp 105-107oCbp 280-281oC
mp -42oCbp 115oC
mp -47oCbp 155oC
Bifunctional compounds
NH
O
N OH
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Contrast with Nucleic Acid Bases (A, T, C, G, U) – Specific!
N N
NN
NH2
H
N N
NNH
O
NH2
H
N
NH
O
O
H
N
NH
O
O
HN
N
O
NH2
HThymine (T)
Guanine (G)Adenine (A)
Uracil (U)Cytosine (C)
* *
*
*
*
Pyrimidines (like pyridine):
Purines
(DNA only) (RNA only)
* 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!
NH N
NN
O
N
H
H
HNHN
O
N
H
H
G C
2 lone pairs inplane at 120o toC=O bond
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 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
G + CKa
G C
get equilibrium constant,
G = -RT ln K = H-TS
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• Molecular recognition not limited to natural bases:
Create new architecture by thinking about biology i.e., biologically inspired chemistry!
Forms supramolecular structure: 6 molecules in a ring
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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…
– Interesting because H-CN/CN- is probably the simplest molecule that can be both a nucleophile & electrophile, and also form C-C bonds
NH N
NN
NH2
NH3 + HCN
Adenine
Polymerization of HCN
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Mechanism?CN NH
H+
NHN
H
NH
NN
H
H NH
C N
N
H
HNH
NH
N
H+
NH
N
N NH
N
H
NH H+
NN
NN
H
NH2
NH3
H+
NN
NN
NH2
H
H
HH
+
NN
NH
N
NH2
H
H+
tautomerization
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N
NH3
N N
N H
HC
G, U, T and C
(cyanogen)
(cyanoacetylene)
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 • We’ve seen it as an acid & an H-bond acceptor• Lone pair can act as a nucleophile:
N R X N+
R
NX
O
N
O
+SN2
+ +
N
O
NH2
PhN
O
NH2
PhN
O
NH2
Ph
HH
++
aromatic, but +ve charge
electron acceptor:electrophile
"H-"
reduction
(like NaBH4)
non-aromatic,but neutral
[O]
oxidation
e.g. exp 2: benzyl dihydronicotinamide: R = PhCH2
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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:
• NAD or related structure may have controlled redox chemistry long before enzymes involved!
NH
CN
NH
CN
N
NH2
O
Diels-Alder
[O],hydrolysis of CN
1% yield
electrical discharge
CH4 + N2 + H2
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Another example of N-Alkylation of Pyridines
NHN
NNH
O
O NN
NN
O
O
CH3
CH3
CH3
Caffeine
This is an SN2 reaction: stereospecific with INVERSION
R
NH
RCH3
S+
Met
Ad R
N
R
CH3 SMet
Ad+ +
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