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


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


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


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.


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%


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


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


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


!


Mistakes Can Happen

OO

O OH

O

OMeO

OO

O

OMe

OH

OO

hexacyclinol


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.


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


Structure Proof

!


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


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


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 %


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



• 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


EXTREMELY TEDIOUS



• LRMS alone?• MW = 130; less certainty à many possible formulas• rule of 13?


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.



• 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)



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


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)




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?



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


• incorporation of elements other than C & H can influence calculation

C10H17NON → CH

C11H18Oignore

C11H18 units of unsaturation = 3

C8H12O2Cl2 X → H

C8H14O2ignore


C18H15PP → CH


18 - 142

24 - 182

40 - 162

= 2

= 3

= 12


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

organic structure determination -...

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