Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0023 92

2. Mass spectra of double-bonded groups

73

phenylisocyanate O=C=NPhCž as the base peak. N Me substitution changes the base peak to the diene fragment N -(2-propenylidene)methylamine, probably because of a shift of the ionization potentials. The fragmentation of the saturated compounds is more complex and allows the differentiation of the stereoisomers. The same authors586 study also the fragmentation of four norbornane/ene di-exo- and di-endo-fused 1,3-oxazin 2(1H)-ones and four 1,3-oxazines-2(1H)-thiones. The results are so far similar in that it is again possible to differentiate among the saturated compounds, whereas the unsaturated molecules allow no distinction. The use of CI as a softer ionization technique reveals some differences. It might well be that initially the difference in structure is maintained, but the small barrier to isomerization asks for especially mild ionization techniques. Hints in this direction may be taken from the work of the group of Vainiotalo587, where four diastereoisomeric camphane-2,3-diols were synthesized and their mass spectrometric behavior studied. Electron impact ionization spectra are within reasonable limits identical and stereochemical effects are weak when NH3, i-C4H10 or CH4 are used as CI reagents. The situation is much more favorable when the CID spectrum of the ammonium adduct [M C NH4]C is measured. The study of this adduct, possible with the CID spectra for its main fragment [M H2 C NH4]C , may allow a differentiation of the stereoisomers. Labeling experiments show that the two hydrogen atoms come from the hydroxyl groups.

Rice, Dudek and Barber588 were the Þrst to show that the major fragmentation in the electron impact spectrum of uracil was the RDA reaction with a loss of HNCO (or RNCO) from positions 2 and 3. Reiser589 proved this not to be always the case, depending on the substitution. An alkyl group with two or more carbon atoms in position 2 gives rise to a [M C4H7]C ion that often forms the base peak. The RDA reaction can be used to differentiate between 2- and 4-thiouracils, and between 1- and 3-Me and Ph substituted uracils. Traldi and coworkers590 studied the inßuence of different substituents R in position 5 of uracil on the metastable spectrum (R D H, F, Cl, Br, I, OH, CF3, Me). For all substituents except R D OH the ÔRDAÕ peak [M HNCO]Cž forms the base peak with >80% of the total intensity. For OH as substituent, [M HN(CO)2]Cž is of comparable intensity. They assume the reaction sequence given in Scheme 21, where positions 3 and 4 as well as 2 and 3 are eliminated in the RDA reaction, contrary to the proposition of the authors cited above. The reason is that the metastable spectra of the [M HNCO]Cž fragments are different for the different neutral precursors: for R D OH and CH3, exclusively CO is eliminated; for R D Cl and Br, HCN is the neutral fragment lost; for R D F and CF3, the loss of both of these fragments is observed; this is also true for R D I, but in addition IC and CIC are formed, probably because of their low ionization energy; with R D H, [ M HNCO H]C , [ M HNCO HCO]C and COCž are additional fragments of comparable intensity. Therefore several [M HNCO]Cž and/or mixtures thereof must be formed according to the substituent of the uracil. This is underlined by the very different values of T0.5 that vary between 50 and 1100 meV according to the substituent.

Nelson and McCloskey591 studied the collision-induced dissociation of protonated uracil and some of its derivatives using extensive isotopic labeling with D, 13C, 15N and 18O. The principal fragment in the CID spectrum of the protonated uracil molecular ion MHC is again the ion resulting from a RDA reaction, [MH HNCO]C , followed in importance by [MH NH3]C , but the spectra of the labeled uracils conÞrm the suspicion advanced in the paragraph above that several pathways for the RDA reaction are possible even for the unsubstituted molecule. For the principal fragments the following pathways are determined (for the numbering see Scheme 22): [MH NH3]C : 7% N(1), 95% N(3); [MH H2O]C : 50% O2, 50% O4; [MH HNCO]C : 10% N 1 C CO 2 , 87% N 3 C CO 2 , 3%N 3 C CO 4 ; [MH NH3 CO]C : 90% N 3 C CO 4 , 10% N 3 C CO 2 ; [MH H2O CO]C : 100% CO 2 C O4 . Most of the minor fragments are also formed

74							Tino Gaumann¬
							N		O		N
							•	N		− HNCO	O +
							R + O				•
										− NCO •	R
											N
	N		O								O +
6	1	2						O+
5	4	3 N					N•			R	H
R
	O							N	− HNCO		N•
							R
							O			R
											O +
							SCHEME 21

in highly site-speciÞc processes. The Þrst question to answer is where the protonation takes place. Hass, Mezey and Ladik592 calculate that the two oxygen atoms should have about the same probability to be protonated. This seems to be a general feature593. However, an observation by Kenttamaa¬594, that in the moment of the collision process isomerizations may take place, makes the question somewhat academic. The Þndings of Nelson and McCloskey591 are summarized in Scheme 22: Several initial isomers are assumed; in three of them a ring opening (k/l) between two consecutive atoms k and l takes place before fragmentation sets in. This explains the loss of H2O and NH3 as primary fragmentation, whose sum amounts to about 80% of the RDA reaction. A small percentage of the primary ions fragments further in often clean processes, coupled with hydrogen transfer, but deuteration of positions 5 and 6 indicated that some hydrogen exchange between these positions and the heteroatoms takes place before elimination of the neutral fragments. The authors studied also the inßuence of substitution in the pyrimidine ring: 2-thiouracil, 4-thiouracil, 2-thiothymine, as well as 3-methyluracil and a series of C-5-substituted uracils (Me , OH, CH3O ). The results, taken cum grano salis, are similar. It may be mentioned that the mass spectrum of the deprotonated negative ion of uracil (m/z 111) seems to be simpler, consisting of only two ions, m/z 67 and m/z 42, as is demonstrated by Sakurai, Matsuo, Kusai and Nojima595.

Nelson and McCloskey596 studied also the collision-induced fragmentation of protonated adenine (Scheme 23), again labeled with 15N, 13C and D. Four main primary

reactions are determined: [MH NH3]C : 55% N(1), 45% N(6); [MH NH2CN]C : 100% N 1 C N 6 ; [MH HCN]C : 90% N 1 C C 2 ; NH4C : 90% N(1) retained in

the ion. There are many secondary reactions; this makes it uncertain to determine the fragmentation paths. Up to three consecutive losses of HCN from MHC and two from [MH NH3]C are observed. This is rather typical in nitrogen heterocycles597. The latter ion loses also C2N2 and NH2CN, but the isotopic distribution of the fragment ions is complicated, indicating different possible reaction pathways. The CID spectra for 1-,

2. Mass spectra of double-bonded groups

75

	H
	N	O
6	1	2
		2/3
5	4	3N
	+OH
	H	+
	N	OH

3 /4

NH

O

H2	O
N
+
	1/2
	NH

O

H

N O

RDA

NH

+OH

H	O+				H				O+
N					N
											− H2 O(4 )
	NH							NH2			− N(3 )H3
OH					O
	H
	N	OH
								− H2 O(2 )
	NH							− N(3 )H3
	O +
	H2	O+
	N
	NH							− N(1)H3
	O
	NH								− HC(6 )N
				O
									− (CO)(4 )
	+
									− C(4, 5)HNO
		N							− C(4, 6)HNO

H

+OH

SCHEME 22

2-, 7- and N6-Me adenine were also studied. These are analogous to adenine except for the loss of Me, which however is a minor process for 7-Me-adenine. A review of the mass spectrometry of nucleic acid constituents up to 1992 is given by McCloskey and Crain536.

The RDA fragmentation can also be of diagnostic value in more complex molecules. Couladouros and Haroutounian598 demonstrate that the electron impact ionization mass spectra of 6-carbamoyloxy-3-oxo-3,6-dihydro-2H-pyrans show a weak molecular peak, but a base peak of m/z 84 resulting from a RDA reaction and a subsequent fragmentation. The three main fragmentation pathways are given in Scheme 24 (R1 D Ph S, Ph S(O), Ph SO2; R2 D Me, Et). The fragmentation for oxazoendiones is similar, but three fragments are formed, shown in Scheme 25; their relative intensity is a function of the substituents (same R1 and R2; in addition R2 D OMe).

76									Tino Gaumann¬
C2 H2 N+			−HCN
						C3 H3 N2 +							C3 HN2 +						C2 H3 N2 +
								−C2 N2						−HCN							−HCN
			−NH2 CN								−HCN					C H N +											+
CHN +						C H N +																		C H N
2			5					3	4					4			2		3					3	4	3
								−NH3									−NH3						−HCN
								NH2
			+						6				N
NH4 +						HN					5		7												+
				1										8				−HCN				C4 H5N4
			2						3		4		9
													N
									N
													H										−NH2 CN
											−NH2 CN
													+			−HCN						C H N +
									C H N
									4		4	3									3		3	2

−HCN

C2 H2 N+

SCHEME 23

The fragmentation of negative organic ions is reviewed by Bowie599,600. It turns out that negative ions do not easily undergo a RDA reaction. For example, substituted cyclohexenes, the classical case for positive ion RDA, will not undergo this fragmentation. Since in negative ion spectroscopy the main reaction is the cleavage to an oxygen atom, dioxin containing 1,3- and 1,4-oxygen atoms do undergo a RDA fragmentation. This is shown by Bowie and Ho601 for nitro-2H, 4H-1,3- and -2,3-dihydro-1,4-benzodioxins. The relative abundance of peaks produced by the RDA reaction shows that the extent of the reaction is largely dependent upon the position of the nitro group. The order observed is 7-NO2 > 5-NO2 × 6-NO2 ¾ 8-NO2. It seems that the importance of the reaction is mainly determined by the relative ease of cleavage of the second bond.

Oßoxacin, 9-ßuoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo 2,3-dihydro-7HH-py- rido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, is a DNA gyrase inhibitor that displays potent antibacterial activity. Routine molecular mass determination of oßoxacin by negative chemical ionization mass spectrometry with methane as reagent gas by Burinsky, Dunphy, Alves-Santana and Cotter602 revealed the astonishing fact that only two ions, the molecular anion m/z 361 and a fragment m/z 319, are present. MS/MS experiments conÞrmed that the fragment must result from a RDA reaction where C N and C O bonds are cleaved (Scheme 26). CID showed only one additional fragment, [M C3H6 C2H5F] ž , resulting from an additional loss from the piperidine ring. Both the NCI mass

		2. Mass spectra of double-bonded groups			77
		R1			O
			+
			+
			O	O
R1			Me		O
				NHR2
	+
		RDA
			R1
	O		+
CH3
	O		O	+	[OCONHR2 ] •
			Me
	O		O
	O
	NHR2	RDA
			O	+	R1
			O
m/z 84	− R2 N = C = O		O		+
		O
				O	O
		O	NHR2		Me
		NHR2

SCHEME 24

spectrum and the daughter ion MS/MS spectrum for the molecular anion of des-ßuoro- oßoxacin exhibit a fragment that corresponds to the RDA reaction. This shows that the presence of ßuorine is not necessary for this fragmentation behavior, although the ßuorinesubstituted ring possesses a considerable positive electron afÞnity.

Etinger and Mandelbaum603 report what they call the Þrst examples of negative-ion RDA fragmentation in a carbocyclic system. The diones Z-1, Z-2 and Z-3 shown in Scheme 27 exhibit highly stereospeciÞc RDA reactions in positive ion electron ionization and in chemical ionization mass spectra537. The negative chemical ionization of Z-1 exhibits practically no fragmentation. The same is true for CID with Ar as collision gas

78		Tino Gaumann¬
R1
	+
		R1					+
	O
Me				+ O = C= CH2	+ O		N
							R2
O
				O		O
O	N		Me
		R2
	O
		SCHEME 25
		O	O	−
	F
				OH
	N	N
N		O
Me		CH3
		− C3	H6		O	O	−
			F
							OH
			N		N
		N		O
		Me

SCHEME 26

for energies below 60 eV. At higher energies, m/z 172 is the most abundant fragment beside [M Me] . The epimeric E-1 exhibits an even higher CID stability and only [M Me] can be observed. The same is true for Z-2 and E-2. In the spectra of the nitro-substituted diones Z-3 and E-3 more fragments can be seen in the negative chemical ionization spectra, but the RDA fragment is only observed in the cis-isomer Z-3. Because of the high stereospeciÞcity the authors assume a concerted mechanism for the RDA reaction.

2. Mass spectra of double-bonded groups

79

O

−

•

O

Z − 1

O

−

•

O X

Z − 2 X = NH2

Z − 3 X = NO2

O

−

+

O

m/z 172

O

−

H

O

E − 1

O

−

+

O X

X = NH2 m/z 187

X = NO2 m/z 217

O

−

H

O X

E − 2

E − 3

SCHEME 27

80	Tino Gaumann¬

XI. ACKNOWLEDGMENTS

It is a pleasure for the author to dedicate this review to Hs. H. Gunthard¬ on the occasion of his 80th birthday and to Daniel Stahl on his 55th birthday as recognition of lifelong friendship and encouragement. I wish to thank my collaborators mentioned in the text for many fruitful discussions and help.

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