Spectrometric Study of the Nitrile-Ketenimine Tautomerism

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Hindawi Publishing Corporation International Journal of Spectroscopy Volume 2009, Article ID 408345, 18 pages doi:10.1155/2009/408345

Research Article Spectrometric Study of the Nitrile-Ketenimine Tautomerism

Hebe Saravı´ Cisneros, Sergio Laurella, Danila L. Ruiz, Agustın´ Ponzinibbio, Patricia E. Allegretti, and Jorge J. P. Furlong

LADECOR (UNLP), Division´ Qu´ımica Organica,´ Departamento de Qu´ımica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Calle 47 y 115, 1900 La Plata, Argentina

Correspondence should be addressed to Jorge J. P. Furlong, [email protected]

Received 13 October 2008; Revised 17 February 2009; Accepted 8 June 2009

Recommended by Craig J. Eckhardt

Mass spectrometry is used to evaluate the occurrence of the nitrile-ketenimine tautomerism. Mass spectra of two diﬀerently substituted nitriles, ethyl-4,4-dicyano-3-methyl-3-butenoate and diethyl-2-cyano-3-methyl-2-pentenodiate are examined looking for common mass spectral behaviors. Ion fragmentation assignments for speciﬁc tautomers allow to predict the presence of the corresponding structures. Additionally, the mass spectrum and nuclear magnetic resonance spectra of ethyl-4,4-dicyano- 2,2-diethyl-3-methyl-3-butenoate and that of the corresponding amination product support the occurrence of the ketenimine tautomer in the equilibrium.

Copyright © 2009 Hebe Sarav´ı Cisneros et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction anion formation and not of nitrile-ketenimine tautomerism [4]. Few reports have been found on the occurrence of nitriles Additionally, in the IR spectra of these compounds, in equilibrium with the corresponding tautomers, the keten- absorption bands between 2100 and 1500 cm−1 which could imines. Some studies where enolization of nitriles takes be expected if any ketenimine had been present were not place have been found [1–3]. Among these tautomeric observed [5]. compounds the most interesting ones were those which A highly enantioselective direct dialkyl allylic elec- involveamethylenehydrogenγ to the nitrile group and trophilic functionalization by addition of diethyl azodicar- electron-acceptor groups as –CN or –COOR (Scheme 1)[3]. boxylates to alkylidene cyanoacetates and malononitriles The majority of nitriles appear to favour strongly the (commercially available organocatalysts) has been demon- cyano form in this equilibrium [1]. Kasturi et al. [2]havecar- strated, and can be applied to other electrophilic addition ried out the study of the UV absorption spectra of several 1,2- reactions [6]. dicyano esters and 1,1,2-tricyano compounds with a view to Tautomerism studies are notoriously relevant in various demonstrate the presence of nitrile-ketenimine tautomerism. biologically important systems, and spectrometric methods, They have synthesized several condensation products of mainly NMR, have been used [7–22]. β-ketoesters with malononitrile and ethyl-cyanoacetate in Mass spectrometry has already demonstrated to be useful connection with the synthesis of heterocyclic compounds. for the study of prototropic tautomerism (keto-enol, amide- From the analysis of the UV spectra in ethanol and in imidol, amine-imine, etc. [23–49]). Some of those processes ethanol/sodium hydroxide solution there was observed a are really difficult to be studied by the NMR, where the hyperchromic effect on the band around 355 nm (detectable solvent plays a key role. Many times interesting tautomeric only in polar hydroxylic solvents) that could be assigned to structures are not detected by this technique which might the presence of the ketenimine structure [3]. be not the case of mass spectrometry since tautomerism Contrarily, the long wavelength UV absorption band occurs in the gas phase previous to ionization. This is why present in the spectra of some alkylidene malononitriles this methodology has been chosen to study the nitrile- and cyanoacetates has been claimed to be a consequence of ketenimine equilibrium trying to find experimental evidence 2 International Journal of Spectroscopy

N NH NH

H3C C H3C C H2C C

CC C C C C

1 1 1 H2C R HC R H2C R

C OCH2CH3 C OCH2CH3 C OCH2CH3

O O O Nitrile Ketenimines

R: CN or COOCH2CH3

Scheme 1: Nitrile-ketenimines equilibria.

N N

H3C C H3C C HOAc/NaOAc CC C O + H2C Benzene − H2C R H2O H2C R

C OCH2CH3 C OCH2CH3

O O (E or Z)

R: CN or COOCH2CH3

Scheme 2: Synthesis of the selected nitriles. about the occurrence of the ketenimine tautomer through general preparation procedure [52], and it was recrystallized the interpretation of mass spectral peaks of selected nitriles. up to constant melting point (163-164◦C). In order to get further support for the occurrence of the ketenimine tautomeric form, it has been resourced to 2.2. Structural Determinations additional experimental evidence as it is the case of an electrophilic addition reaction that can only take place 2.2.1. Gas Chromatography-Mass Spectrometry-Single through an specific tautomer (ketenimine). Amination was Quadrupole. These determinations were performed by selected and although a mechanistic study of amination of injection of methanol solutions (1 μL, 100 μg/mL aprox.) ketenimines is lacking, it is known that amination of keten- in an HP 5890 Chromatograph coupled to an HP 5972 A imines forms amidines. By high-level ab-initio calculations mass selective detector (unit mass resolution). An HP5-MS Sung et al. [50] concluded that amination of ketenimines capillary column (30 m × 0.25 mm × 5 μm) has been used proceeds via amine addition across the C=N bond rather with Helium as the carrier gas (0.6 mL/min in column, split ◦ than the C=C bond, followed by tautomerization to form the ratio 1 : 30). The temperatures set points were 200 C in the ◦ ◦ amidine product. They have observed an intermediate vinyli- split injector, 300 C in the interface, 185 C in the ion source ◦ dendiamine by low-temperature proton NMR spectrometry. and the oven ramp started at 40 C(5minutes),andended ◦ ◦ The main purpose of the present work is to find at 290 Cwithaheatrateof20 C/ min. The electron energy experimental evidences for the occurrence of the ketenimine was 70 eV, and the pressure in the mass spectrometer was −5 structure in equilibrium with the nitrile tautomer. lower than 10 torr, thus precluding ion molecule reactions. Isotopic exchange was performed by dissolution of the corresponding compound in methanol-d1.Massspectra 2. Experimental Part were analyzed one hour after dissolution. The relevance of spectrometric data as a predictive 2.1. Synthesis of Nitriles and Amidine. The ethyl esters of tool in regard to tautomeric equilibria depends mainly on the alkylidene malononitrile and the alkylidene cyanoac- the fact that the contribution due to tautomerization of etate, ethyl-4,4-dicyano-3-methyl-3-butenoate and diethyl- molecular ions in the gas phase does not take place or can 2-cyano-3-methyl-2-pentenodiate, were synthesized accord- be ignored. The importance of this point comes from the ing to the condensation procedure of Cope-Knoevenagel physicochemical properties of ionic and radical species, quite [51, 52](Scheme 2). different from the neutral ones. This could be the reason The ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate of possible distortion of results and loss of the desirable was synthesized according to literature procedures [53]. predictive power of the methodology. The synthesis of the corresponding amidine (prepared by It has been demonstrated, in the case of keto-enol reaction with diethylamine) was carried out according to the tautomerism of a variety of carbonyl and thiocarbonyl International Journal of Spectroscopy 3 compounds [38–49], that there is no significant intercon- 106 version of the tautomeric forms in the gas phase follow- 9000 66 133 ing electron impact ionization in the mass spectrometer 7000 (molecular ions, M+., do not seem to undergo unimolecular 78 tautomerization), and, even more surprising, for GC/MS 5000 experiments, once the solvent is separated after injection in 150 Abundance 3000 51 the injection port of the gas chromatograph, tautomerism 64 122 178 mechanisms (intermolecular, unimolecular) would not seem 1000 107 123 to take place even with no GC separation (under the selected 0 experimental conditions). These conclusions are supported 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 by temperature studies at the ion source (negligible effect) m/z and at the injection port of the gas chromatograph with a Figure 1: Mass spectrum of ethyl-4,4-dicyano-3-methyl-3- shifting effect in agreement with the corresponding heats of butenoate. tautomerization [42, 47]. In fact, this process would take place very fast under the working conditions in the GC. Separation of tautomers in the analytical column is 2D gradient-selected COSY and multiplicity-edited HSQC frequently very difficult; consequently the different pathways experiments to helpwith the assignment of signals. All 2D of fragmentation of the tautomeric forms have to be used spectra were recorded with the same spectrometer. for identification of individual tautomers. For this reason Vendor provided pulse sequences were used throughout and because of the high similarity between MS (commercial the work. databases) and GC/MS spectra, analytical separation has not been considered critical for the present work. Analogously, 2.3. Computational Procedure. Theoretical calculations offer it is thought that most of the conclusions could be useful to an interesting approach to define relative stabilities of analyze spectra registered with mass spectrometers equipped compounds that participate in different kinds of equilibria. with direct insertion probes. That is why AM1 calculations [54] were performed on the ethyl-4,4-dicyano-3-methyl-3-butenoate using the standard Hyperchem package [55]. Since it has been resorted to heat 2.2.2. Gas Chromatography-Mass Spectrometry-Ion Trap. of formation values in order to rationalize experimental find- These determinations were performed by injection of ings and the AM1 technique has been specially parameterized methanol solutions (1 μL) in a Thermo Quest Trace 2000 to reproduce this sort of experimental data, the authors think coupled to Finnigan Polaris ion trap detector (unit mass that this choice is a sensible one for the molecular set under resolution) under the same experimental conditions already consideration. Besides, previous computations obtained for mentioned for the single quadrupole GC/MS system. This this kind of studies have given quite sensible results in order instrumentation was utilized to confirm proposed fragmen- to correlate experimental and theoretical data, so that it is tation pathways by CID (collision induced dissociation) deemed that is not necessary to appeal to higher levels of using Helium as the damping gas, a CID voltage of 4–7 eV molecular electronic structure sophistication. and an excitation energy of 0.3–0.45 (values were optimized for each ion transition). These experiments were done by selecting a precursor ion from the full-scan spectrum and 3. Results and Discussion carrying out the corresponding MS/MS product ion scan. The relative stabilities of all possible tautomers for the ethyl- 4,4-dicyano-3-methyl-3-butenoate have been estimated by 2.2.3. Nuclear Magnetic Resonance. 1H NMR spectra in semi-empirical calculations (AM1 level), and the results are CDCl3,wererecordedwithaVarianMercuryPlusspec- shown in Table 1. trometer operating at 4.7 T. The typical spectral conditions The predicted most likely tautomerization process were as follows: spectral width 3201 Hz, acquisition time 4.09 involves the conversion of the nitrile-keto form I to the seconds and 16 scans per spectrum. Digital resolution was ketenimine-keto III. The energy barrier to form tautomers 0.39 Hz per point. Deuterium from the solvent was used II, V and, VI indicates that they are likely to occur in some as the lock and TMS as the internal standard. Sample con- extent while tautomerism involving the methyl moiety (IV) centration was 20 mg/mL. Measurements were performed at and the double tautomerization process (VII and VIII)seem 25◦C. to be less likely. 13C proton decoupled and gated decoupled spectra were The mass spectrum of ethyl-4,4-dicyano-3-methyl-3- recorded with the same spectrometer from CDCl3 solutions butenoate is shown in Figure 1. at 25◦C. The spectral conditions were as follows: spectral From the assignment of the main fragment peaks it width 10559 Hz, acquisition times 1.303 seconds and 1000 seems clear the occurrence of the ketenimine form because scans per spectrum. Sample concentration was 40 mg/mL, there exist fragment ions that can only be explained from and digital resolution was 1.29 Hz per point. that tautomer. The proposed fragmentation mechanisms are A standard one-dimensional (1D) proton NMR spec- supported by the data although it should be noted that there trum and a carbon spectrum with broad-band proton is no absolute proof for them since there might be alternative decoupling were run of each sample, supplemented by pathways that are not eliminated by these experiments. 4 International Journal of Spectroscopy

Table 1: Heats of formation and relative stabilities of the tautomeric forms of ethyl-4,4-dicyano-3-methyl-3-butenoate by AM1 calculations.

−1 −1 Tautomer ΔHf, kcal mol ΔΔHf,kcalmol N

H3C C I O C C −24,18846 0

C CH2 C

H3CH2CO N NH

H3C C

C C II −6,2391 17,94936 H C C

C O N

H3CH2CO NH

H3C C III O C C −8,38831 15,80015 C C C

H3CH2CO H N NH

H2C C IV O C C 3,558174 27,746634

C CH2 C

H3CH2CO N N

H3C C V HO C C −8,176637 16,011823 C C C

H3CH2CO H N N

H3C C

C VI H3CH2CO C −8,175188 16,013272 C C C

HO H N NH

H2C C VII HO C C 17,81065 41,99911 C C C

H3CH2CO H N NH

H2C C

VIII H3CH2CO C C 17,98366 42,17212 C C C

HO H N

The peaks at m/z 104, 105, 106, 132, 133, and 150 can be ion would come from that one at m/z 106 by loss of HCNH justified from both tautomeric forms (Scheme 3). through hydrogen rearrangement. The fragment ion at m/z 66 can only be justified from the In case that tautomerization involving the enol from the ketenimine form (Scheme 4). The ion at m/z 106 can also be ester moiety occurs, there are no evident pathways for the formed by the other ketenimine form (Scheme 3(b)) which formation of m/z 66 and the ions in the range m/z 104–106. can render the fragment ion at m/z 66 (Scheme 4(b)). The fragmentation pathways were confirmed by GC/MS- It seems that the fragment at m/z 78 could be assigned to IonTrapexperiments(Table 2): the ions at m/z 66, 132, 133, the ketenimine since the only possible alternative to form this and 150 are generated from the molecular ion at m/z 178; the International Journal of Spectroscopy 5

CH3 C

H3CH2CO CC N N C CH C+

rH CH3 C CH C O H N 3 α H3CH2CO CC CC

m/z 178 −CH3CH2O C CH C CH C

O NH NH + C +

O m/z 133

CH3 C N

H2C O CC CH3 C C CH C H2C 2 CC O NH + CH C

C + NH

− C2H4 α

− CO i

CH3 C

O CC N

C CH2 C CH3 C N α O NH CC −CO2 + CH3 C CH C CC + NH CH2 C m/z 150 m/z 105

NH + m/z 106

∗McLaﬀerty’s conventions are followed in all fragmentation schemes: half arrows indicate the movement of a single electron as observed for α-cleavage mechanisms (α) and radical-site hydrogen rearrangements (rH), full arrows are used for inductive cleavage mechanisms (i) indicating the transfer of an electron pair. The use of double arrows indicates the equilibrium between tautomers as neutral species in the gas phase. It does not intend to imply tautomerim between charged species.

(a) Scheme 3: Continued. 6 International Journal of Spectroscopy

+ + H N NH NH + H2C C H2C C H2C C

C C rH C C α CC −CH CH O HC C HC C 3 2 HC C

CONH CONH C NH

H3CH2CO H3CH2CO O m/z 133 m/z 178

NH NH

H2C C H2C C

C C + CC

H HC C HC C

H2C CONH C NH +

H2C O O

− C2H4 α

NH NH

H2C C H2C C α C C + CC+

H2C C H2C C

CONH NH

O m/z 150 m/z 106

−C2H4 α

NH NH

H2C C H2C C rH α C C H3CH2CO C C m/z 133 H3CH2CO −CH3CH2O C CH C + C CH C

O H N O NH + m/z 178 m/z 178

(b) Scheme 3: Continued. International Journal of Spectroscopy 7

N N N

H3C C H3C C H3C C

C C α i C C CC − −CH3CH2O CO H2C C H C C H2C C 2 + + CON + C N N O O m/z 105 m/z 133 H2C CH3

NH NH NH

H3C C H3C C H3C C

C C C C C C

HC C HC C HC C + + + C O N C N N

O O

H2C CH3

NH NH NH

H2C C H2C C H2C C

C C C C CC

H C C H2C C H2C C 2 + + + CON C N N

O O

H2C CH3 (c) H C CN H CH2 CN H2C CN 2 + rH, i i C C CC CC H2C O − −CH3CH2OH CO + H3C C CH2 CN H2C CN C CH2 CN + m/z 132 O O m/z 104

NH NH NH

H3C C H2C C H2C C + H2C O C C C C C C + H3C C CH CN C CH CN HC CN + O O NH

H2C C + H2C O CC

H3C C CH2 CN

O + H CH2 CN HO + O CC rH, α C CH2 CN C CH2 CN O − H2C C C H C CH3 O 2 m/z 88

H2C CH3 CN (it is not observed)

Scheme 3: Continued. 8 International Journal of Spectroscopy

N N

H3C C H3C C

C C rH, α C C

−C2H4 H2C C H2C C + + CON COHN

O H O m/z 150 H2C CH2

NH NH

H3C C H3C C C C C C HC C HC C + C O N + C OH N O H O

H2C CH2

NH NH

H C C 2 H2C C

C C C C

H C C 2 H2C C + + CON C OH N

O H O

H2C CH2

(d) Scheme 3: Fragment pathways involving both tautomeric forms of ethyl-4,4-dicyano-3-methyl-3-butenoate.

123 179 Table 2: MS2 data for ethyl-4,4-dicyano-3-methyl-3-butenoate. 9000 151 Precursor ion (m/z) Relevant product ions (m/z) 7000 97 178 150, 133, 132, 106, 105, 104, 66 5000 150 106, 78, 66 124 52 133 105 Abundance 3000 78 107 67 132 104 65 106 134 1000 106 78, 66 0 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 m/z Figure 2: Mass spectrum of diethyl-2-cyano-3-methyl-2- pentenodiate. Scheme 5 shows the main fragment ions that can be generated from all tautomeric structures. Not only the + molecular ion but also the ions (M–C2H4) and (M–C2H4– + ion at m/z 106 comes from that one at m/z 150; the ion at m/z CO2) are not observed. It should be pointed out that the 105 arises from the ion at m/z 133; the ion at m/z 104 comes initial hydrogen transfer in Scheme 5(a) can occur to the from the ion at m/z 132; the ions at m/z 66 and 78 arise from carbonyl oxygen atom to render the ions at m/z 153 and 152. that one at m/z 106. In that case the ion at m/z 180 should be represented as an Figure 2 shows the mass spectrum of diethyl-2-cyano-3- equilibrium between the protonated ester and the protonated methyl-2-pentenodiate. nitrile by hydrogen rearrangement. International Journal of Spectroscopy 9

H N + H2C C

C C rH, α HC C

−H C C CHCOOCH2CH3 NH CONH 2 C O

HC + H2CCH3 m/z 178 C

NH m/z 66 NH rH, α H2C C

− H3CH2CO C C H2C C CHCOOCH2CH3

C CH C+

O H N m/z 178

(a) NH NH

H2C C C α C C C + −CH2 CCH2

H2C C C

NH NH m/z 66 + m/z 106

(b)

Scheme 4: Fragmentation pathways involving ketenimine tautomers of ethyl-4,4-dicyano-3-methyl-3-butenoate.

Table 3: MS2 data for diethyl-2-cyano-3-methyl-2-pentenodiate. from that one at m/z 152; the ions at m/z 134, 151, and m/z 67 arise from the ion at m/z 179; the ions at m/z 107, 123, Precursor ion (m/z) Relevant product ions (m/z) and 106 come from the ion at m/z 151; the ion at m/z 106 180 152, 124 also arises from the ion at m/z 134; the ion at m/z at 79 is 179 151, 134, 123, 107, 106 generated by the ions at m/z 107 and 123; the ions at m/z 69, 152 124 96, and 97 arise from that one at m/z 123. 151 123, 107, 106, 97, 96 In order to better support the specificity of the proposed 134 106 fragmentation pathways, isotopic exchange with methanol- 123 97, 96, 79, 69 d1 was carried out for the ethyl-4,4-dicyano-3-methyl-3- 107 79 butenoate. The corresponding mass spectrum is shown in Figure 3. As observed, not only expected shifts are observed (m/z The ion at m/z 153 is not significant maybe due to the 66-67, m/z 78-79, m/z 104-105, m/z 105-106, m/z 106- lower probability of the double hydrogen rearrangement. 107, m/z 132-133, m/z 133-134, m/z 150-151, m/z 178- The m/z 124 can be explained from the nitrile form 179) but also m/z 68, m/z 80, m/z 108, m/z 135, m/z 152, (Scheme 6). and m/z 180 are present. This can be explained by taking The fragment ion at m/z 67 can only be explained from into consideration the equilibria in Scheme 8.Asmentioned the ketenimine form (Scheme 7). before, the enol form from the ester seems to be unable to The following fragmentation pathways were confirmed generate the clusters at m/z 66–68 and m/z 104–108. by GC/MS-Ion Trap experiments (Table 3): the ion at m/z To get additional supporting evidence for the occur- 152 comes from that one at m/z 180 and the ion at m/z 124 rence of the ketenimine tautomer that involves the free 10 International Journal of Spectroscopy

H2C CH3 H2C CH3 H2CCH3

O O O

H3C C O H3C C O H3C C O rH α O CC O CC CC −CH3CH2O C CH C+ C CH C HC C

O H N O H NH C NH + +

H2C CH3 H2C CH2 O

m/z 180 rH

H2C CH3

O H2CCH3

H3C C O O

O CC H3C C O

C CH2 C C C

O NH HC C +

H2C CH2 +C NH

−C2H4 O −CO α, α 2 −CO i

H CCH 2 3 H2C CH3

O O

H3C C O H3C C O

CC C C

H2C C HC C + NH + NH m/z 153 m/z 152 (a) H3C H3C H3C + + + H O CH2 HO CH2 HO CH2

H C C O H2C C O 2 α, α H2C C O rH O CC O CC C C −CH3CH2O C CH C C CH C HC C

O NH O NH C NH

H2C CH3 H2C CH3 O

m/z 225 m/z 180

rH, α

− H3C CH3CH2O H3C + O H O CH2 HO CH2

C CH C O H2C C O

H3CH2CO CC C C

H2C C HC C

NH C NH + m/z 225 O

(b)

Scheme 5: Continued. International Journal of Spectroscopy 11

H3CH2CO H3CH2CO H3CH2CO

H3C C O H3C C O H3C C O α i CC CC CC −CO −CH3CH2O

H2C C H2C C H2C C + + CON C + N N

H3CH2CO O m/z 180 m/z 152

H3CH2CO H3CH2CO

H3CH2CO H3C C O H3C C O H C C O CC CC 3

CC HC C HC C

+ + HC C CONH C NH + NH H3CH2CO O m/z 180 m/z 152

H3CH2CO H3CH2CO H3CH2CO H2C C O H2C C O H2C C O CC CC CC

H2C C H2C C H2C C + + CONH C+ NH NH H3CH2CO O m/z 180 m/z 152

(c)

H3CH2CO + H3C C O O CC − CH + 3CH H3C C 2O H2C C α CC i H3C CO N + H2C C −CO CC H3CH2CO C O N H2C C

H3CH2CO m/z 180 CO N

H CH CO 3 2 m/z 152

(d) For the other carbonyl group and for the three tautomers.

Scheme 5: Continued. 12 International Journal of Spectroscopy

H3CH2CO H3CH2CO H3CH2CO

H CH2 C O H2C C O H2C C O + rH, i i H3CH2CO CC − CC CC CH3CH2OH −CO

C CH2 C H C C H2C C 2 + O N C O N N + m/z 179 m/z 151

H3CH2CO H3CH2CO H3CH2CO H3CH2CO

H3C C O H2C C O H2C C O H2C C O + + H3CH2CO C C CC CC H3CH2CO CC CH C CH C HC C HC C C 2 C + O NH O O NH +C NH NH (it does not proceed)

(e)

CH2CH3 O H3CH2COOCHC + H3CH2CO H O H3CH2COOCHC C + + C C rH, i i C CH C O CC − −CO CH3CH2OH H3C C

O CC H3C C N H3C C m/z 179 N m/z 151 N

CH2CH3 O + H3CH2COOCHC H CH COOCHC H3CH2CO H O 3 2 C+ + C C C CH C O CC H2C C O CC H2C C NH H2C C NH

CH2CH3 + H3CH2CO O

C CH C O

O CC

H C C 3 (it does not proceed) NH

(f) For the other ester moiety. Scheme 5: Continued. International Journal of Spectroscopy 13

H2C CH2 O O O + + O H O C CH2 C H2C C + C CH C O CC CC rH, αα − O CC C2H4 H3C C −CO2 H3C C

H3C C m/z 151 N m/z 107 N

m/z 179 N −CO i − i O CO

H2C C CH2 + − + α CC CH3CH2O α O CC −CO2 H3C C O H3C C + m/z 79 N O C CH C m/z 123 N

O O H3C C

m/z 134 N rH, α C C − + + C2H4 H2C O H2C O −CO i α −CNH C C O C CH CC H2C CH2 + H C H2C CC 2 CN α m/z 96 O H −CH CH O H H3C C 3 2 α,i C CH −CN m/z 106 O + N + H C O C C 2 C+ i CCO H3C CN H2C −CO

H3C m/z 151 CCO m/z 69 (only possible from H3C m/z 97 nitrile form)

(g)

Scheme 5: Fragmentation pathways involving all tautomeric structures of diethyl-2-cyano-3-methyl-2-pentenodiate.

+ + O O H3C

H3C C O H3C C + O CC

C C CH2 α CC i C CH C −CO −CH3CH2O H2C C H3C H C C 2 O H N C O N CON H2C CH3

O CH2 O CH2 m/z 152

H3C H3C rH m/z 180

H3C

O CCH

C CH C −C2H4 + m/z 124 O H N

H2C CH2

m/z 152 Scheme 6: Fragmentation pathway involving the nitrile form of diethyl-2-cyano-3-methyl-2-pentenodiate. 14 International Journal of Spectroscopy

H2C CH3 + H O

H2C C O rH, i, α O C CCNH O C C + m/z 67

H3C C CH C

H2C O NH rH, i, α

H2C CH3 + O H O

H3C C CH C O

H2C O CC

H2C C

NH Scheme 7: Fragmentation pathway involving the ketenimine form of diethyl-2-cyano-3-methyl-2-pentenodiate.

H3C R H3C R H3C R CH3OD CC CC −CH3OH CC

HC C HC C DHC C

CONH COND CON

O O O

H2C CH3 H2C CH3 H2C CH3

H3C R H3C R

CC CC CH3OD

DC C −CH3OH DC C

COND CONH

O O

H2C CH3 H2C CH3

Scheme 8: H/D isotopic exchange for ethyl-4,4-dicyano-3-methyl-3-butenoate (R = cyano).

methyl group, the synthesis of ethyl-4,4-dicyano-2,2-diethyl- Ketenimines react with nucleophiles as amines and 3-methyl-3-butenoate was carried out. This product was alcohols [50], so that the electrophilic addition to the alkene analyzed not only by MS (Figure 4) but also by NMR moiety of the ketenimine can be carried out thus obtaining (Table 4) demonstrating that, for this compound, the lack of the corresponding amidine, that is possible only if that the methylene group does not preclude tautomerization to structure is present (Scheme 10). the ketenimine form. Equimolar amounts of ethyl-4,4-dicyano-3-methyl-3- The ion at m/z 163 constitutes the base peak, and it seems butenoate and diethyl amine in diethyl ether were mixed and to be only explainable from the ketenimine (Scheme 9). allowed to react until detection of product formation. After GC/MS-Ion Trap experiments showed that this ion is recrystallization the reaction products were identiﬁed by 1H generated directly from the molecular ion at m/z 234. and 13CNMR(Table 5). From the corresponding analysis it After isotopic exchange with methanol-d1 the fragment turns that both ketenimines are present (Scheme 1), that is ion at m/z 163 shifts to m/z 164, that constitutes a supporting consistent with mass spectrometric results of the diethylated evidence for the proponed fragmentation pathway. alkylidene malononinitrile, where the base peak can only International Journal of Spectroscopy 15

H3C CN H2C CN

CC CC H3CH2C H3CH2C C CN C C H3CH2C + H CH C CO 3 2 CO + NH

H3CH2CO H CH CO 3 2 m/z 234

H2C H2C

C C CN CN C C H3CH2C H3CH2C CH rH C C C H3CH2C H3CH2C CO NH CO NH + + H

H2CH2CO H2CH2CO

−(CH3CH2)2CH

H C 2 C C CH2 C NH

H2C C O O +

+ C C H2 H2 N C C C C H2C C H C C 2 NH C NH C

H2C C H2C C O O O + O

m/z 163 Scheme 9: Proposed fragmentation pathway involving the ketenimine form of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate.

C CHCOOCH2CH3 H3CH2C

C C + NH

H CH C C CH3 3 2

N N

C CHCOOCH2CH3 C CHCHOOCH2CH3

CH C + CH C

HN C CH3 HN C CH2

N(CH2CH3)2 N(CH2CH3)2

Scheme 10: Reaction of ethyl-4,4-dicyano-3-methyl-3-butenoate with diethylamine involving the ketenimine Form. 16 International Journal of Spectroscopy

Table 4: Nuclear magnetic resonance spectra (1Hand13C) of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate.

(a) (b) (b) (a) (a) (b) (b) (a) N CH CH N H3CH2C CH2CH3 H3CH2C 2 3 (e) (d) (e) (d) OCH CH C OCH CH (l) C (j) C (k) 2 3 (l) (j) C (k) 2 3 C (h) C (m) CC CC (n) (i) (l) O O CH C C 3 (g) CH2 (c) (f) N HN (CDCl ) (ppm): 0.9-1.0 (t, J: 7.5 Hz (a)); 1.1-1.2 (t, J: 7.2 Hz (d)); 1,7-1.8 (q, J: 7.5 Hz (b)); 2,1 (s, (c)); 4.1 (q, J: 7.2 Hz (e)); 1HNMR 3 δ 4.9-5.2(2d, J: 2.2 Hz (f)); 7.6 (s, (g)). (CDCl ) (ppm): 11.2 (a); 14.1 (d); 18.7 (c); 29.5 (b); 37.5 (h); 48.6 (j); 62.0 (e); 80.2 (m); 113.2 (f); 116.5 (l); 140.8 (i); 174.3 13CNMR 3 δ (k); 179.8 (n); 190.3 (g).

Table 5: Nuclear magnetic resonance spectra (1Hand13C) of the amination products of ethyl-4,4-dicyano-3-methyl-3-butenoate.

N O N O (h) (g) (k) C HC C (k) C H2C C (i)(n) (i) (n) CH C OCH2CH3 CH C OCH2CH3 (l) (c) (e) (d) (m ) (f) (e) (d) (j) HN C (j) CH3 HN C CH2

N(CH2CH3)2 N(CH2CH3)2 (b) (a) (b) (a) (CDCl ) (ppm): 1.1-1.2 (m, ((a) and (d)); 1.7 (s, (c)); 2.6 (q, J: 7.4 Hz (b)); 2.9 (s, (g)); 3.2 (s, (i)); (4.2 (q, J: 7.2 Hz (e)); 1HNMR 3 δ 5.0–5.2 (m, (f)); 5.7 (s, 1H, (h)); 8.4 (s, (j)). (CDCl ) (ppm): 14.1 (d); 14.4 (a); 18.7 (c); 38.7 (b); 40.7 (g); 60.1 (e); 62.5 (i); 111.6 (f); 114.6 (h); 124.2 (k); 140.1 (m); 149.1 13CNMR 3 δ (l); 166.5 (n); 169.0 (j).

107 be justiﬁed by the ketenimine involving the methyl group 134 9000 (the ethyl groups on the methylene make impossible the formation of the other ketenimine tautomer). 7000 67 108 The bidimensional NMR allowed to conﬁrm the assign- 5000 79 ments (see experimental part). In addition, the preparation 52 Abundance 3000 152 and detection of the amidines from the nitrile in neutral 64 132 180 medium is also a strong indication of the presence of the 1000 123 ketenimine structures in the equilibrium. 0 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 m/z 4. Conclusions Figure 3: Mass spectrum of ethyl-4,4-dicyano-3-methyl-3- butenoate after isotopic exchange with methanol-d1. Thereportedevidencesfoundbymassspectrometryin regard to the occurrence of the nitrile-ketenimine tau-

163 tomerism have been supported through isotopic exchange, MS2 and reactivity experiments (amination reaction and 9000 8000 NMR determinations). AM1 calculations were consistent 7000 with the relative importance of the ketenimine tautomer for 6000 one of the compounds here studied. Although for a long 5000 234 time the value of mass spectrometry as a tool to predict the 4000 177 191 219 occurrence of prototropic interconversions in the gas phase Abundance 3000 178 2000 has been questioned, nowadays there is enough experimental 205 1000 79 106 117 134 145 235 work that supports this approach. In this sense, there are 53 66 90 0 some key aspects to keep in mind: there should be speciﬁc 60 80 100 120 140 160 180 200 220 240 assignments of fragment ions to tautomeric structures, m/z tautomerization is not supposed to proceed between ionic Figure 4: Mass spectrum of ethyl-4,4-dicyano-2,2-diethyl-3- species, and this approach does not intend to constitute a methyl-3-butenoate. quantitative tool. International Journal of Spectroscopy 17

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