Organic Structure Determination -...
Transcript of Organic Structure Determination -...
Organic Structure Determination
The Beginning
O
OHHO OH
OHHO
D-glucose(1891)
O
HO
HO
NMe
morphine(1925)
N
O
N
H
H
O
strychnine(1948)
• structure determined by chemical methods
Organic Structure Determination
Common Spectroscopic Methods
1. Nuclear Magnetic Resonance (NMR)C-H framework
2. Infrared Spectroscopy (IR)functional groups
3. Ultraviolet Spectroscopy (UV-Vis)conjugation
4. Mass Spectrometry (MS)molecular weight; chemical formula
Organic Structure Determination
Spectroscopic Determination
O
OO
O
O
HOOH
H HOH
H HH
O O
OO
O
OO O
HHH
HMe
HH
HHHH HH
H H HHMe Me OH
OHMe
Me
HO
ciguatoxin(Yasumoto, 1989)
N
OH
OO
OH
OH
OHO
niizalactam AAbe, 2015
O O
O OMeMe
OOMe OMe
Cl
Me
OH
HOHO
HO
O
O
O
H
HO
O
HO
spirastrellolide A(Anderson, 2001)
38
26
Organic Structure Determination
Bullvalene – a fluxional molecule
Ault J. Chem. Ed. 2001, 78, 924. bullvalene
interchange by Cope rearrangement; 1,209,600 distinct structures;
C CC
C
CCC
CC CCC
C CCC
etc.etc.
CC CC
etc. CC CC
etc.
Organic Structure Determination
Stereochemistry of the Vinylcyclopropane Rearangement
Baldwin J. Am. Chem. Soc. 1994, 116, 10845.
Δ
biradical vs. concerted mechanism? determination of product distribution and rate constants support biradical process
DD
D
DDD
D
D
D
D
D
D
D
D
D
D
D
D
(si + sr = 63%) ar = 13% ai = 24%
(ar + ai = 37%) sr = 23% si = 40%
Organic Structure Determination
Determination of Peptide Secondary Structure
Kessler J. Am. Chem. Soc. 2001, 123, 6678.
BrHN N
H
HN N
H
HN N
HO
O
O
O
O
H O
O
HN
O
NHCH3
Ph
model hexapeptide
Organic Structure Determination
Binding Studies
Nicolaou, Chazin, Gomez-Paloma J. Am. Chem. Soc. 1998, 120, 7183.
S S S
OHO
OO
H
NH O
O
OOHO
OHHNMeO
S
O
O
I
OMeOMeO
OHMeOHO
HN
O
OMe
calicheamicin γ1
head to tail oligosaccharide dimer
Organic Structure Determination
Mistakes Can Happen
O
O
O
HOHO
HO
HO O
O
O
HOHO
HO
HO
reported structure revised structure
amphidinolide A
MeO
O HN
O
HN
O
N O
O
O NMe
O
OHHMeO
O HN
HN
OO
O NMe
O
OHH
halipeptin AS
N
reported structure revised structure
!
Organic Structure Determination
Mistakes Can Happen
OO
O OH
O
OMeO
OO
O
OMe
OH
OO
hexacyclinol
reported structure revised structure
isolation: Gräfe J. Antibiotics 2002, 814.1st synthesis: LaClaire Angew. Chem., Int. Ed. 2006, 45, 2769.NMR prediction: Rychnovsky Org. Lett. 2006, 8, 2895.2nd synthesis: Porco Angew. Chem., Int. Ed. 2006, 45, 5790.
retraction: Angew. Chem., Int. Ed. 2012, 51, 11661.
Organic Structure Determination
Mistakes Can Happen In YOUR Lab
HCO2Me
OR
CO2Me
OR
CO2Me
OR
HOR
CO2Me
Diels-Alder Diels-Alder
original report:J. Am. Chem. Soc. 1988, 110, 631.
revision:Tetrahedron Lett. 1989, 30, 433
SiMe
Me Pd cat.
O
EtOEtO
O SiMe2Ph
EtO
O SiMe2Ph
original report:J. Am. Chem. Soc. 1997, 119, 698.
revision:Tetrahedron Lett. 2001, 42, 3775
Organic Structure Determination
Structure Proof
!
Organic Structure Determination
General Approach
(Empirical Formula)
Molecular Weight
Molecular Formula (units of unsaturation)
Functional Groups
Structural Features(fragments à connectivity à stereochemistry)
Final Structure?
Empirical Formula
Elemental Analysis
• also known as combustion analysis• provides quantitive information on atom types à relative percentages• use to calculate empirical formula (gives lowest integer ratio of atoms present)
how does it work?
CxHyOz + O2 xCO2 + (y/2)H2Oknownmass
measure quantites ofeach formed
Δ
excess
1. weigh compound exactly (2-5 mg)2. wrap it in tin cup3. place in vacuum chamber4. evacuate air, then fill with O25. drop into 1000°C furnace (O2 atmosphere)6. measure what comes off by GC (CO2, H2O, NO2)
general procedure
Empirical Formula
Elemental Analysis
% O = 100% - 64.6% - 10.8%= 24.6%
% oxygen then determined by difference:
report
Organic Structure Determination
Elemental Analysis
• unknown compound à determine empirical formula
sample: 64.6% C 10.8% H 24.6% O
1. convert % to mole fraction:
2. convert grams to moles:
3. determine empirical formula:from above
divide by smallest #
convert to whole # ratio if needed
note: empirical formula is NOT the same as molecular formula!
assume 100g of sample, then64.6% C = 64.6g C10.8% H = 10.8g H24.6% O = 24.6g O
64.6g C / (12.01g/mol) = 5.38 moles C10.8g H / (1.01 g/mol) = 10.7 moles H24.6g O / (16.00 g/mol) = 1.54 moles O
C5.38H10.7O1.54
C3.49H6.95O1 à C3.5H7O1
C7H14O2
Organic Structure Determination
Elemental Analysis
O
OCO2Et
Chemical Formula: C14H20O6Elemental Analysis: C, 59.14; H, 7.09; O, 33.77
OO
reported as:
Anal. Calcd for C14H20O6: C, 59.14%; H, 7.09%. Found: C, 59.03%; H, 7.12%.
• known compound à proof of purity
error: ± 0.4 mass %
Organic Structure Determination
Molecular Weight / Molecular Formula
• back to unknown: 64.6% C, 10.8% H, 24.6% O à C7H14O2
• MW = 130; supports molecular formula C7H14O2 vs. C14H28O4, etc.
Low Resolution Mass Spectrometry (LRMS) – MW determined to the nearest amu
!
parention
Organic Structure Determination
Molecular Weight / Molecular Formula
• LRMS alone? à can determine MW to nearest amu• MW = 130; less certainty à many possible formulas• Rule of 13 (Pavia section 1.5) à help to identify possible formula
Low Resolution Mass Spectrometry (LRMS) – MW determined to the nearest amu
EXTREMELY TEDIOUS
Organic Structure Determination
Molecular Weight / Molecular Formula
• LRMS alone?• MW = 130; less certainty à many possible formulas• rule of 13?
Low Resolution Mass Spectrometry (LRMS) – MW determined to the nearest amu
on-line formula calculators: http://www.chemcalc.org/mf_finderhttps://www.stolaf.edu/depts/chemistry/courses/toolkits/380/js/masscalc/http://www.massbank.jp/MassCalc.html
text book Tables: • Silverstein Spectrometric Identification of Organic Compounds. Chapter 2, Appendix A. Formula
Masses (FM) for Various Combinatinos of Carbon, Hydrogen, Nitrogen and Oxygen.
• McLafferty, Turecek Interpretation of Mass Spectra, Table A.7 Common elemental compositionsof molecular ions.
Organic Structure Determination
Molecular Weight / Molecular Formula
• use mass obtained to determine possible formulas in absence of elemental analysisformula calculators, tables in text to suggest possibilities as with LRMS
High Resolution Mass Spectrometry (HRMS) – MW determined to four decimal places
!!
MW = 130 (Silverstein, Appendix A)
Organic Structure Determination
Molecular Weight / Molecular Formula
HRMS Rates: Old Dominion University COSMIC
• if molecule has odd # of N, molecular mass will be an odd number • if molecule has even # of N, molecular mass will be an even number
Nitrogen Rule
!
NH2N NH2
C8H17NMW: 127
C5H14N2MW: 102
Organic Structure Determination
Units of Unsaturation
• also known as Index of Hydrogen Deficiency, Unsaturation Number, etc.• indicates number of p bonds and/or rings present in the molecule
Saturated Alkane = CnH2n+2
C6H14 C6H12C6H12
loss of 2H when add πbond or form ring
saturated alkane(CnH2n+2)
units of unsaturation = expected H (saturated) – observed H2
(n = # of carbons)
Organic Structure Determination
Units of Unsaturation
units of unsaturation = expected H (saturated) – observed H2
example 1: C7H14 à 1 unit of unsaturation à one ring or 1 double bond
example 2: C9H12 à 4 units of unsaturation à one ring, 3 double bond?
Organic Structure Determination
Units of Unsaturation
oxygen: no change to calculation (ignore O); also ignore S
C7H14O à calculate as above so: (16-14)/2 à 1° unsaturation
halogen: replace each X by an H
C7H13Br à C7H14 so: (16-14)/2 à 1° unsaturation
nitrogen: replace each N by CH; do same for P and B
C7H13N à C8H14 so: (18-14)/2 à 2° unsaturation
units of unsaturation = expected H (saturated) – observed H2
• incorporation of elements other than C & H can influence calculation
C10H17NON → CH
C11H18Oignore
C11H18 units of unsaturation = 3
C8H12O2Cl2 X → H
C8H14O2ignore
C8H14 units of unsaturation = 2
C18H15PP → CH
C19H16 units of unsaturation = 12
18 - 142
24 - 182
40 - 162
= 2
= 3
= 12
Organic Structure Determination
Units of Unsaturation: examples
#1
#2
#3
The Electromagnetic Spectrum
gammarays x-rays ultraviolet
(UV) visible Infrared(IR) microwaves radiowaves
short wavelengthhigh frequency
high energy
long wavelengthlow frequency
low energy
UVvisibleIRradiowaves
200 - 400 nm400 - 800 nm2.5 - 15 µm1 - 5 m
wavelengths of interest
Can relate frequency (υ) to energy E = hυ
Planck's constant: h = 6.63 x 10-34 J • s
wavelength (λ): distance from one wave maxima to the next
frequency (υ): number of maxima that pass by a point in a given time
amplitude: height of wave measured from midpoint to maxima
Spectroscopy and the Electromagnetic Spectrum
1. Nuclear Magnetic Resonance (NMR)radio waves à nuclear spin transitions
2. Infrared Spectroscopy (IR)infrared radiations à bond vibrations
3. Ultraviolet Spectroscopy (UV-Vis)ultraviolet (visable) radiation à electronic transitions
4. Mass Spectrometry (MS)molecule bombarded with high energy electons
EMradiation
gammarays x-rays ultraviolet
(UV) visible Infrared(IR) microwaves radiowaves