Projections - McMaster University
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Transcript Projections - McMaster University
Projections
O
H
OH
1
H
OH
2
HO
O
1
OH
2
3
HO
4
OH
5
OH
HO
3
O
OH
4
OH
5
CH2OH
OH
CH2OH
6
OH
6
HO
4
OH
HO
6
5
H
O
OH
OH
OH
O
OH
3
Haworth of ribose
convential Fischer
turn on
side
1
2
OH
OH
OH
Haworth
OH
More Reactions of Sugars
1)
Reactions of OH group(s):
a)
Esterification:
O
O
OAc
OH
HO
HO
O
O
O
AcO
AcO
OH
HO
AcO
O
acetic anhydride:
reactive acid derivative
b)
O
penta-O-acetyl--D-glucopyranose
Ethers:
SN2
R-OH
+
Ph
Br
R-Ph
Benzyl ethers
b) Ethers (con’t)
HO
O
Ph3CBr
OH
TrO
O
OH
S N1
OH
via stable
carbocation
OH
OH
OH
(cf malachite
green)
**SELECTIVE: steric hinderance
only 1o reacts
Tr = trityl =
c) Acetals
O
TrO
O
TrO
OH
O
OH
H+
OH
OH
(eg. TsOH)
Acetonide: best for 5 - membered rings
requires cis OH groups
O
O
c) Acetals (con’t)
HO
O
O
O
Ph
H
OH
TsOH
OMe
OH
OH
H
O
Ph
OH
OMe
O
OH
Benzaldehyde: prefers 6-membered ring
the 2 OH's can be cis or trans (provide they are diequatorial)
WHY?
Me2CO: requires R2 (Me) to be axial in 6membered ring
R1
R2
O
O
O
PhCHO: can have R2 = H & Ph can be
equatorial
* new stereocentre
These reactions are used for selective protection of one
alcohol & activation of another (protecting group chemistry)
HO
O
TrO
T
O
TrCl
OH
T
OH
1° alcohol is most
reactive protect
first
TrO
O
TrO
T
O
H2 O
OH
activate 2o
alcohol
CH3SO2Cl
inverts stereochemistry
at C3
O
T
O
S
O
reactivate
MeSO2Cl
AZT
TrO
O
T
+
TrO
O
N N N
OMs
SN2
N3
HO
T
O
HCl
remove Tr
N3
T
e.g, synthesis of sucrose (Lemieux, Alberta)
OPG
OPG
OPG
OH
O
PGO
PGO
OPG
OH
PGO
O
PGO
Activate anomeric
centre as oxonium
ion
• Can only couple one way—if we don’t protect, get all
different coupling patterns
• Yet nature does this all of the time: enzymes hold
molecules together in the correct orientation, BUT the
mechanism still goes through an oxonium ion (more on
this later)
Selectivity of Anomer Formation in Glycosides
• Oxonium ion can often be attacked from both Re & Si
faces to give a mixture of anomers.
+
Si face
O
Re face
• How do we control this?
HO
HO
HO
O
HO
Ac2O
OH
(Cf Exp 2)
AcO
AcO
AcO
O
OAc
AcO
HBr/AcOH
AcO
-anomer is favored
due to strongly ewithdrawing Br
AcO
AcO
O
AcO
Br
-bromide
AcO
AcO
AcO
MeOH
O
AcO
Br
Ag2CO3
AcO
AcO
AcO
AcO
+
O
O
O
O
AcO
AcO
O
O
+
cis-fused dioxolenium ion--must be axial!
MeOH
AcO
AcO
AcO
O
OMe
AcO
-glycoside activity
This reaction provides a clue to how an enzyme might
stabilize an oxonium ion (see later)
Examples of Naturally Occurring di- & oligoSaccharides
Maltose:
2 units of glucose
a β sugar
α glycoside
1,4-linkage
Lactose (milk):
galactose + glucose
a β sugar
β glycoside
1,4-linkage
OH OH
O
HO
OH
OH
O
HO
O
OH
OH
HO
Sucrose (sugar):
glucose + fructofuranose
a β sugar
α glycoside
1,2-glycosidic bond
HO
HO
O
OH OH
O
CH2OH
OH
O
CH2OH
α-1,6-glycosidic bond
Amylopectin (blood cells):
an oligosaccharide
α-1,4-glycosidic bond
Structure Determination of Sugars
• The following is an example to review & expand your
knowledge of NMR
– Consider the question of glycoside formation:
HO
HO
HO
HO
O
HO
H3O+
OH
MeOH
HO
HO
O
OMe
HO
or anomer?
See NMR spectra of both anomers:
They are different-diastereomers have different spectra,
but which is which?
-methyl glucopyranose
HO
HO
HO
O
HO
OMe
H
-methyl glucopyranose
HO
HO
HO
O
HO
H
OMe
These spectra are rich in independent information:
1) Chemical shift, :
•
Reveals functional groups (see chart)
•
Depends on inductive effects, # of EWGs & bonds
Inductive effects
Cl CH3
CH3
Si CH3
e.g.
+
Chemical
shift (ppm)
-
0
0
-
+
# of EWGs
e.g. glucose– anomeric H is most downfield since 2 O atoms
attached to C have more of an effect that 1 atom. we can
assign the anomeric proton in the both spectra of α and β
methyl glucoside
bonds –alkenes, aromatics, C=O, etc
2)
Integrals
•
3)
NMR is quantitative e.g. glycosides—area under anomeric
signal = 1; area under the signal at 3.3 = 3x bigger, 3
protons, must be a CH3 group
Multiplicity
•
Protons communicate their spins over 1, 2 or 3 bonds—
reveals # of neighbors
e.g. CH3-O group: a singlet, one line, no neighbors—nearst
neighbor is 4 bonds away
e.g. anomeric proton: a doublet, 2 peaks, one neighbor that is
3 bonds away (recall n neighbors, n +1 peaks)
4)
Coupling Constant
•
Distance between peaks in a multiplet is J, coupling
constant—depends on geometry
(con’t)
4)
•
•
e.g. α glycoside: 2 peaks are 4.650-4.632 = 0.018 ppm apart
spectrometer frequency = 200 MHz
J = 0.018 ppm x 200 MHz = 3.6 Hz
For the β-glycoside, J = 8.0 Hz
Different J values reflect different geometries:
H1 – C1 – C2 – H2 = 60° in α, = 180° in β
J depends on geometry according to Karplus curve:
At 60°, J is small
180°, J is large
J reveals the geometry, i.e., the
stereochemistry of the glycoside
dihedral H-X-X-H
• But, looking at the spectra, note that the CHOH protons
at C-2, C-3, C-4, C-5 & C-6 are all overlapping.
• hard to measure each J value—How to use NMR to
get a complete structure?
• What about a very complex case, i.e., sucralose, the
sweetener in splenda:
HO
HO
HO
O
HO
HO
Cl2
O
O
HO
OH
Cl
HO
O
Cl
O
HO
HO
OH
OH
SUCROSE
Cl
O
OH
SUCRALOSE
• Where are the chlorines? Which anomer is formed?
Pyranose &/or furanose ring?
A challenging structure—need advanced NMR methods
Quick review of NMR theory & Pulse
NMR:
Not an important part of exams, but may
help on questions for assignments
Modern NMR spectrometers use pulse NMR, rather than
CW; advantages are:
1) Can acquire full spectrum in 2-3 seconds, rather than
2-3 min
2) Can add together data from many pulses—improves
signal/noise
3) Can combine 2 or more pulses—allows magnetic
billiards—
e.g. make different CH, CH2, CH3 groups have different
phase
e.g. 2D NMR –COSY- to determine which H’s are
coupled to one another
e.g. 3D NMR –to determine protein structures &
conformation in solution
How does it work? We’ll do a simple treatment
apply magnetic field
random fields associated
with spinning nucleus
e.g. 1H (I = 1/2)
13C
"
nuclei align with or against
field:quantised spin + or - 1/2
Energy gap between states:
-1/2
E
E
+1/2
no
field
Bo
Applied field
More spin states in low energy (Boltzmann) = net absorption
= resonance (signal!)
Mechanism of Absorption:
pulse - excites all magnetic nuclei simultaneously
on
off
at equilibrium:
most alinged
with field
emits electromagnetic radiation at
different frequencies
relaxation - nuclei return
to original
spin state
FID = free induction decay
2-3 sec
Points about FID
a) A sin wave with frequency -o (the difference in the
frequency of RF signal & frequency emitted from
nucleus) chemical shift
b) Decays with time as relaxation occurs (i.e., nuclei lose
excitation)
Watch the FID on the 200 MHz when you get your
spectrum!
Transform FID to
Frequency
domain
-o (i.e. )
• In a real spectrum, the FID is a complex mixture of
different sine waves with
– Different frequencies -o, ie., different
– Different intensities, i.e. integral
– Different relaxation rates, ie, different widths
• FT resolves it all—based on a mathematical formula by
Fourier (French mathematician 18th C)
• FIDs can be added together to improve S/N: this is
essential for e.g. 13C NMR
FID 1
Add together: S/N
improves by 2
FID 2
In general, S/N improves by 2 for each 22 = 4 times the number of
scans
• Going back to the spectrum of xxx: we have a
problem—which CH is which & what pairs are coupled
together?
• Use COSY, a 2D technique that plots vs on x X y
A
axes
B
Cross-peaks
show coupled
pairs
Diagonal peaks
B
A
• Very useful—can work way around rings & assign
protons
COSY: How does it Work?
• Collect a series of spectra with different delay times:
FID 1
FID 2
Different magnetization vector than FID 1
• Series of FIDs & spectra are collected and a 2D contour
map is generated (contour plot)
Contour plot:
• H vs H
• like a map
• if two 1H aren’t coupled = no
crosspeak
A
Cross-peaks
show coupled
pairs
B
Diagonal peaks
B
H1
A
H2
• COSY tell us which protons are coupled together!
Back to Sucralose
• Assign anomeric H in the pyranose
• Look for cross-peak → H-2
• Look for cross-peak from H-2 → H-3 etc
• Extremely useful in determining chemical shift
assignment
– Once each H in sucralose is assigned, you can measure the
coupling constants, J
e.g. H-1, d, J = 4 Hz =5.37
1 or both of the H1 & H2 are equatorial
H-2 3.83 (by COSY), dd, 4 & 10 Hz J2,3 = 10 Hz
• H2 & H3 are both axial
• H1 is equatorial:
H
O
H
HO
H
OH
O
• Try 6-membered ring
• Note the 2 diastereotopic protons at H6—see the
coupling in the COSY spectrum
– The chemical shifts are very close since they exhibit strong
coupling
– This is common with diastereotopic protons
– Also see example in the benzoin lab (exp 7)
Other 2D Experiments
• TOCSY
– Correlates all the spins in a coupled spectrum, e.g. sucralose
– 2 spin sets: the pyranose & the furanose rings
• NOESY
– Nuclear overhauser effect
– Correlates protons that are close in space
A relaxes &
transfers magnetization
to B
A
B
A
B
A
B
irradiate
Bo
A
slight increase
or decrease in
signal to B
• NOESY is a 2D version—useful for protein
conformations
13C
NMR:
• Usually acquired with protons decoupled
– Simplifies spectra: each C 1 signal
– Increased sensitivity: big nOe 1H 13C & singlet for each C (no
coupling)
• But lose info use DEPT
– Singlet, but with attached proton info
• Even better: Combine 1H & 13C (HSQC/HMBC)
– Cross-peaks show which H is attached to which C (HSQC) or
adjacent H’s (HMBC)
– Very useful in structure determination