welcome to 3ff3! bio-organic chemistry jan. 7, 2008
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Welcome to 3FF3!Bio-organic Chemistry
Jan. 7, 2008
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• Instructor: Adrienne Pedrech– ABB 417– Email: [email protected] website:
http://www.chemistry.mcmaster.ca/courses/3f03/index.html
Lectures: MW 8:30 F 10:30 (CNH/B107)– Office Hours: T 10:00-12:30 & F 1:00-2:30 or by
appointment – Labs:
2:30-5:30 M (ABB 302,306) **Note: course timetable says ABB217 2:30-5:30 F (ABB 306)
Every week except reading week (Feb. 18-22) & Good Friday (Mar. 21)
Labs start Jan. 7, 2008 (TODAY!)
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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 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. Feb. 29, 2008 at 7:00 pmMake-up test: TBDAssignments: Feb.6 – Feb.13 Mar.7 – Mar.14 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 notes 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 cell (focus of 3FF3)
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° 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:
1) How do chemists synthesize these structures?
2) How are they made in vivo?
3) Improved chemistry through 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/inhibiton
6) Catalysis → groups work in concert
7) Replication → turnover
e.g. an enzyme has many turnovers, nucleic acids replicates
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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: HCN + NH3 bases
H2C=O sugars
nucleosides
phosphate
nucleotides
RNA
"RNA world"
catalysismore RNA, other molecules
modern "protein" world
CH4, NH3
H2Oamino acids
proteinsRNA
(ribozyme)
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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 vivo – how is the cell CONTROLLED?
c) 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)
2) Structural principles & characterization(e.g. anomers of glucose, anomeric effect, diastereomers, NMR, Exp 2)
3) Cofactor chemistry – pyridinium ions (e.g. NADH, Exp 3 & 4)
4) Biomimetic chemistry (e.g. simplified model of NADH, Exp 3)
5) Chemical mechanisms relevant to catalysis (e.g. NADH, 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. drugs, dilantin, tylenol, Exp 5,7)
8) 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
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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
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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 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
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 suffice
N HO
H:
e- donor e- acceptor
H-bond acceptor
H-bonddonor
acidbase
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Contrast with Nucleic Acid Bases (A, T, C, G, U) – Specific!
N N
NN
NH2
H
N N
NN
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 Bases (Nucleic)
• Thousands of methods in heterocyclic chemistry– we’ll 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
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?
** 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)
e.g. exp 3: benzyl dihydronicotinamide
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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
electical discharge
CH4 + N2 + H2
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Another example of N-Alkylation of Pyridines
NHN
NNH
O
O NN
NNH
O
O
CH3
Caffeine
This is an SN2 reaction with stereospecificity
R
NH
RCH3
S+
Met
Ad R
N
R
CH3 SMet
Ad+ +
s-adenosyl methionine
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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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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:
OHH
CH2OH
OHOH
O
OHCH2OH
OH
glyceraldehyde (chiral)
dihydroxyacetone(achiral)
Aldose Ketose
glycolaldehyde
Aldose
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• Most sugars, i.e., glyceraldehyde are chiral: sp3 hybridized C with 4 different substituents
The last structure is the Fischer projection:1) CHO at the top2) Carbon chain runs downward3) Bonds that are vertical point down from chiral centre4) Bonds that are horizontal point up5) H is not shown: line to LHS is not a methyl group
OH
OH
H
CHOCHO
OH
OHH
CHO
OH
OHH= =
(R)-glyceraldehyde
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• 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-glyderaldehyde
(+)/d & (-)/l do NOT correlate
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• Glyceraldehyde is an aldo-triose (3 carbons)• Tetroses → 4 C’s – 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)
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Reactions of Sugars1) The aldehyde group:
a) Aldehydes can be oxidized
“reducing sugars” – those that have a free aldehyde (most aldehydes) give a positive Tollen’s test (silver mirror)
b) Aldehydes can be reduced
OH OOH
Ag(I) Ag(0)
NH3
Aldose Aldonic acid
OH OHHNaBH4
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c) Reaction with a Nucleophile
• Combination of these ideas Killiani-Fischer synthesis: used by Fischer to correate D/L-glyceraldehyde with threose/erythrose configurations:
OH OHMeMgBr
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OHOH
CN
OH
CN
OH
CO2H
OH
CO2H
OH
CHO
OH
CHO
-CN +
cyanohydrins(stereoisomers)
H3O+
+
aldonic acids
NaBH4
+
pair of homologousaldoses
Nu, (recallfrom base synthesis)
nitrile hydrolysis
(reduce)
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Reactions (of aldehydes) with Internal Nucleophiles
• Glucose forms 6-membered ring b/c all substituents are equatorial, thus avoiding 1,3-diaxial interactions
O
OHOH
OH
OH
OH
OH
OHOH
OH
O
OHH
O
OH
OH
OH
OH
OH
CH2OH D-glucose
H+
a "hemiacetal"D-glucopyranose
Derivative of pyran
1
2
3
4
5
6
12
3
45
6
=
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• Can also get furanoses, e.g., ribose:
O
H
OHOH
OHOH
OOH
OHOH
OH
O
ribofuranose
like furan
• Ribose prefers 5-membered ring (as opposed to 6) otherwise there would be an axial OH in the 6-membered ring
OOH
OHOH
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Why do we get cyclic acetals of sugars? (Glucose in open form is << 1%)
a) Rearrangement reaction: we exchange a C=O bond for a stronger C-O σ bond ΔH is favored
b) There is little ring strain in 5- or 6- membered rings
c) ΔS: there is some loss of rotational entropy in making a ring, but less than in an intermolecular reaction:1 in, 1 out.
H
O
H
MeO OMe
+ 2 MeOH+ H2O
3 molecules in 2 molecules out
** significant –ve ΔS! ΔG = ΔH - TΔS
Favored for hemiacetal
Not too bad for cyclic acetal
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Anomers
• Generate a new chiral centre during hemiacetal formation (see overhead)
• These are called ANOMERS– β-OH up – α-OH down – Stereoisomers at C1 diastereomers
• α- and β- anomers of glucose can be crystallized in both pure forms
• In solution, MUTAROTATION occurs
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O
OHOH
OH
OH
OH
OH
OHOH
OH
O
OHH
OH
OHOH
OH
OOH
HO
OHOH
OH
OHOH
-D-glucopyranose (19o)
-D-glucopyranose (112o)
Mutatrotation
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In solution, with acid present (catalytic), get MUTAROTATION: not via the aldehyde, but oxonium ion
OOH
O+ O
OHH+
H2O
oxonium ion
• At equilibrium, ~ 38:62 α:β despite α having an AXIAL OH…WHY? ANOMERIC EFFECT
+112o ()[]D
+19o ()
+52.7o
at equilibrium
time
MUTAROTATION
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O
OH
O+
-OH
O lone pair is antiperiplanar to C-O σ bond GOOD orbital overlap (not the case with the β-anomer)
oxonium ion
Anomeric Effect