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1 AFB QO I 2007/08 1 Química Orgânica I Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 2 MS

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Page 1: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

1

AFB QO I 2007/08 1

Química Orgânica I

Ciências Farmacêuticas

Bioquímica

Química

AFB QO I 2007/08 2

MS

Page 2: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 3

Adaptado de:

� Organic Chemistry, 6th Edition; L. G. Wade, Jr.

�� http://www.cem.msu.edu/~reusch/Vihttp://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/MassSpec/masspertualText/Spectrpy/MassSpec/masspec1.htm#ms1c1.htm#ms1

AFB QO I 2007/08 4

Mass Spectrometry

� Molecular weight can be obtained from a very small sample.

� It does not involve the absorption or emission of light.

� A beam of high-energy electrons breaks the molecule apart.

� The masses of the fragments and their relative abundance reveal information about the structure of the molecule. =>

Page 3: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 5

From molecular ions to molecular mass

Chemical

Ionization

MH+

H+

H+

H+

H+

[M+H]+

Weighs one more than

MW

Dislodges an

electron

Electron Impact

M-e• -e•

-e•

-e•-e•

-e•

2e-•

M+•

AFB QO I 2007/08 6

Electron Impact Ionization

A high-energy electron can dislodge an electron from a bond, creating a radical cation (a positive ion with an unpaired e-).

e- + H C

H

H

C

H

H

H

H C

H

H

C

H

H

H

H C

H

H

C

H

H

+ H

H C

H

H

C

H

H

H

+=>

Page 4: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 7

Mass Spectrometry- Ionization

AFB QO I 2007/08 8

Separation of Ions

� Only the cations are deflected by the magnetic field.

� Amount of deflection depends on m/z.

� The detector signal is proportional to the number of ions hitting it.

� By varying the magnetic field, ions of all masses are collected and counted. =>

Page 5: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 9

Mass Spectrometer

=>

AFB QO I 2007/08 10

The GC-MS

=>

A mixture of compounds is separated

by gas chromatography, then identified

by mass spectrometry.

Page 6: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 11

Simple spectra

AFB QO I 2007/08 12

Page 7: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 13

Base peak and molecular ion

=>

AFB QO I 2007/08 14

High Resolution MS

� A molecule with mass of 44 could be C3H8, C2H4O, CO2, or CN2H4.

� If a more exact mass is 44.029, pick the correct structure from the table:

C3H8 C2H4O CO2 CN2H4

44.06260 44.02620 43.98983 44.03740

=>

Page 8: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 15

Molecules with Heteroatoms

� Isotopes: present in their usual abundance.

� Hydrocarbons contain 1.1% C-13, so there will be a small M+1 peak.

� If Br is present, M+2 is equal to M+.

� If Cl is present, M+2 is one-third of M+.

� If iodine is present, peak at 127, large gap.

� If N is present, M+ will be an odd number.

� If S is present, M+2 will be 4% of M+. =>

AFB QO I 2007/08 16

even-electron ionseven-number mass

odd-electron ionsodd-number mass

Ions having anodd # N atoms

even-electron ionsodd-number mass

odd-electron ionseven-number mass

Ions with no nitrogenor an even # N atoms

Page 9: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 17

Even-odd

AFB QO I 2007/08 18

Isotopic Abundance

=>

Page 10: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 19

Mass Spectrum with Sulfur

=>

AFB QO I 2007/08 20

Bromine

Bromine: 50.50% 79Br and 49.50% 81Br

e.g: Br-Br

79 + 79

79 + 81; 81 + 79

81 + 81

Page 11: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 21

Mass Spectrum with Bromine

=>

AFB QO I 2007/08 22

vinyl chloride

Chlorine: 75.77% 35Cl and 24.23% 37Cl

(aprox. 3/4 : 1/4)

Page 12: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 23

Chloropropane

=>

AFB QO I 2007/08 24

methylene chloride

� 2 x Cl

Page 13: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 25

Mass Spectra of Alkanes

More stable carbocations will be more abundant.

=>

AFB QO I 2007/08 26

Fragmentation Patterns

hexyl (m/z = 85), pentyl (m/z = 71), butyl (m/z = 57), propyl (m/z = 43), ethyl (m/z = 29) and methyl (m/z = 15)

Page 14: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 27

Mass Spectra of Alkenes

Resonance-stabilized cations favored.

=>

AFB QO I 2007/08 28

Mass Spectra of Alcohols

� Alcohols usually lose a water molecule.

� M+ may not be visible.

=>

Page 15: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 29

fragmentation patterns

AFB QO I 2007/08 30

alkyl chain: m/z=57, 43, 41, 29 & 27

m/z=29 ion is probably composed of both ethyl and HCO cations

m/z=86 is more abundantLoss of carbonyl substituents by alpha-fragmentation include: - loss of methyl (M-15 at m/z=71) - loss of a propyl (M-43 at m/z=43)

Simetric moleculem/z=57 (loss of an ethyl) m/z=29 (an ethyl cation)

Page 16: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 31

Common Fragment Ions and Neutral Fragments

SH, CH2F33

CH3O31

CH2NH

230

C2H

5, CHO29

C2H

4, CO, H

2CN28

C2H

327

C2H

2, CN26

H3O, F19

H2O18

OH17

CH3

15 amu

compositionm/z

Common Small Ions

CH4O, S32

CH3O31

CH2O30

C2H

4, CO28

C2H

3, HCN27

HF20

F19

H2O18

OH17

CH3

15

H1 amu

compositionmass loss

Common Neutral Fragments

http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/MassSpec/mspec.htm#ms1

AFB QO I 2007/08 32

HI128

I127

C7H

791

HBr80(82)

Br79(81)

CH4CO

260

C4H

957

C4H

856

NO2

46

C2H

4O44

C3H

7, CH

3CO43

C3H

6, C

2H

2O, C

2H

4N42

C3H

5, C

2H

3N41

C3H

339

HCl36(38)

Cl35(37)

H2S34

SH, CH2F33

compositionm/z

Common Small Ions

HI128

I127

HBr80(82)

Br79(81)

SO2

64

C2H

4O

260

C2H

3O

259

C4H

957

C4H

755

C2H

5O45

CO2O, CONH

244

C3H

7, CH

3CO43

C3H

6, C

2H

2O, C

2H

4N42

HCl36(38)

Cl35(37)

H2S33

CH3

+ H2O, HS33

compositionmass loss

Common Neutral Fragments

Page 17: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 33

Some popular cleavages

Cleave β to a heteroatom

(capable of supporting

positive charge)

CH3 CH3

CH3CH3

CH3

C+

CH3

CH3.

Obs. in Mass Spec

+

neutral

+

RORO

RO

:

:Obs. in Mass Spec

Resonance stabilized

neutral

+

+

AFB QO I 2007/08 34

Some examples

Primary alcohols, m/z=31 CH2=OH+

Primary amines, m/z=30 CH2=NH2+

Page 18: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 35

Commonly encountered Electron-Impact fragments

N

CH2+

92

+ +91

H

H

H

H

H

+

77

CH2+

43 H

O

+29

AFB QO I 2007/08 36

McLafferty Rearrangements

Radical cations localized on keto-type oxygen give β cleavage

The mechanism limits this to EI fragmentation

Needs a H atom on a γ sp3 carbon

Ketones, esters, carboxylic acids all give McLafferty products

O+

HR2

R1

• O+

H

OH

R1 R2

•••

+ Loss of

neutral

alkene

The new radical

cation is

stabilized by

resonance

Page 19: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 37

Important example of McLafferty

OH

OH

m/z = 60

+

Seen for primary carboxylic acids

AFB QO I 2007/08 38

Cleavage αααα to C=O groups

O O

O

: .

+

++:

+: :Obs. in mass spec.

Acylium ions are

resonance-stabilized

neutral

CH3C=O+

m/z=43

Page 20: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 39

Example

O

O+

M+• -43; also

tropylium ion

AFB QO I 2007/08 40

Rearangement Mechanisms in Fragmentation (McLafferty)

Page 21: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 41

AFB QO I 2007/08 42

Complexpaterns

Page 22: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 43

Cleave α to Heteroatoms like O, N

O

R

: .

+•

Heterolytic cleavage

R

O:: .

neutral

+

Observed in Mass Spec provided that a

good stabilized carbocation can form

+

AFB QO I 2007/08 44

Rearrangements and fragmentations to give good Carbocations

CH2+

CH

+ CH2

H C

CH2

+

Benzylic

cation

(stabilized

including

“tropylium”

ion m/z=91

Good cleavage β to

aromatic rings

CH+

Page 23: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 45

Example

Bromine

pattern

Tropylium

ion

Br

AFB QO I 2007/08 46

Carboxylic acids

γH present?; can give McLafferty rearrangement to

alkene plus CH2=C(OH)(OH)•+ at m/z=60

Loss of water, especially in CI

Loss of 44 is loss of CO2

m/z=45 suggests O≡C–OH+

Page 24: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 47

Amines

N•+ N+

-R•

R

Cyclic amines will lose adjacent H•, form iminium ion

In CI, ≡NH+ can eliminate adjacent alkene, reprotonate

AFB QO I 2007/08 48

Silyl Ethers

SiO+

•Loss of CH3• from Si

Loss of R• in β cleavage

Loss of •CR3 then CH3• to (CH3)2Si=OH+ m/z=75

Total loss of carbinol to (CH3)3Si+ m/z=73

Page 25: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 49

H transfer in heterosubstitutedAnisoles

OCH3

ORLoss of CH2O

Extra H

transfer

mediated by

adjacent

heteroatom

H

O+

R

H

H

+•

AFB QO I 2007/08 50

Nitroaromatics

N

+

O•

OO

+

Loss of

•N=O

Loss of

C≡O

m/z= 93

(this can

form

from lots

of

different

origins)

CH+Aromatic!

m/z=65

Good test for aryloxy

Page 26: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 51

Sulfur Compounds

Fortunately there is an [M+2]+ of 4% for the natural

abundance of 34S. This is diagnostic for S vs 2x16O

Aliphatic thiols can split out H2S, [M-34]

Alpha cleavage at carbon bearing the sulfur in thiols,

thioethers, similar to ethers, etc.

S+

S+R

-R•

AFB QO I 2007/08 52

The “retro Diels-Alder”Cleavage

+

+•

+•

+

+•

Observed!

Observed!

Typically you see both.

More stable cation will predominate

Also works for hetero-substituted (e.g. make

enol)

Both EI (shown) and in Chemical Ionization.

(protonated molecular ion, cleave, then

reprotonation

Cyclohexenes, with favorable 6-membered transition state. Can include heteroatoms

(N,O, driven by keto-enol like stability.

Page 27: Química Orgânica Iw3.ualg.pt/~abrigas/QOI14a_MS.pdf · Química Orgânica I ... Mass Spectrometry ... The mechanism limits this to EI fragmentation Needs a H atom on a γ sp 3 carbon

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AFB QO I 2007/08 53

An Example from TerpenoidChemistry

+

+

+

∆12-Oleanenem/z 204