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.
Few reports have been found on the occurrence of nitriles in equilibrium with the corresponding tautomers, the ketenimines. Some studies where enolization of nitriles takes place have been found [
Nitrile-ketenimines equilibria.
The majority of nitriles appear to favour strongly the cyano form in this equilibrium [
Contrarily, the long wavelength UV absorption band present in the spectra of some alkylidene malononitriles and cyanoacetates has been claimed to be a consequence of anion formation and not of nitrile-ketenimine tautomerism [
Additionally, in the IR spectra of these compounds, absorption bands between 2100 and 1500 cm−1 which could be expected if any ketenimine had been present were not observed [
A highly enantioselective direct dialkyl allylic electrophilic functionalization by addition of diethyl azodicarboxylates to alkylidene cyanoacetates and malononitriles (commercially available organocatalysts) has been demonstrated, and can be applied to other electrophilic addition reactions [
Tautomerism studies are notoriously relevant in various biologically important systems, and spectrometric methods, mainly NMR, have been used [
Mass spectrometry has already demonstrated to be useful for the study of prototropic tautomerism (keto-enol, amide-imidol, amine-imine, etc. [
In order to get further support for the occurrence of the ketenimine tautomeric form, it has been resourced to additional experimental evidence as it is the case of an electrophilic addition reaction that can only take place through an specific tautomer (ketenimine). Amination was selected and although a mechanistic study of amination of ketenimines is lacking, it is known that amination of ketenimines forms amidines. By high-level
The main purpose of the present work is to find experimental evidences for the occurrence of the ketenimine structure in equilibrium with the nitrile tautomer.
The ethyl esters of the alkylidene malononitrile and the alkylidene cyanoacetate, ethyl-4,4-dicyano-3-methyl-3-butenoate and diethyl-2-cyano-3-methyl-2-pentenodiate, were synthesized according to the condensation procedure of Cope-Knoevenagel [
Synthesis of the selected nitriles.
The ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate was synthesized according to literature procedures [
The synthesis of the corresponding amidine (prepared by reaction with diethylamine) was carried out according to the general preparation procedure [
These determinations were performed by injection of methanol solutions (1
Isotopic exchange was performed by dissolution of the corresponding compound in methanol-d1. Mass spectra were analyzed one hour after dissolution.
The relevance of spectrometric data as a predictive tool in regard to tautomeric equilibria depends mainly on the fact that the contribution due to tautomerization of molecular ions in the gas phase does not take place or can be ignored. The importance of this point comes from the physicochemical properties of ionic and radical species, quite different from the neutral ones. This could be the reason of possible distortion of results and loss of the desirable predictive power of the methodology.
It has been demonstrated, in the case of keto-enol tautomerism of a variety of carbonyl and thiocarbonyl compounds [
Separation of tautomers in the analytical column is frequently very difficult; consequently the different pathways of fragmentation of the tautomeric forms have to be used for identification of individual tautomers. For this reason and because of the high similarity between MS (commercial databases) and GC/MS spectra, analytical separation has not been considered critical for the present work. Analogously, it is thought that most of the conclusions could be useful to analyze spectra registered with mass spectrometers equipped with direct insertion probes.
These determinations were performed by injection of methanol solutions (1
1H NMR spectra in CDCl3, were recorded with a Varian Mercury Plus spectrometer operating at 4.7 T. The typical spectral conditions were as follows: spectral width 3201 Hz, acquisition time 4.09 seconds and 16 scans per spectrum. Digital resolution was 0.39 Hz per point. Deuterium from the solvent was used as the lock and TMS as the internal standard. Sample concentration was 20 mg/mL. Measurements were performed at
13C proton decoupled and gated decoupled spectra were recorded with the same spectrometer from CDCl3 solutions at
A standard one-dimensional (1D) proton NMR spectrum and a carbon spectrum with broad-band proton decoupling were run of each sample, supplemented by 2D gradient-selected COSY and multiplicity-edited HSQC experiments to helpwith the assignment of signals. All 2D spectra were recorded with the same spectrometer.
Vendor provided pulse sequences were used throughout the work.
Theoretical calculations offer an interesting approach to define relative stabilities of compounds that participate in different kinds of equilibria. That is why AM1 calculations [
The relative stabilities of all possible tautomers for the ethyl-4,4-dicyano-3-methyl-3-butenoate have been estimated by semi-empirical calculations (AM1 level), and the results are shown in Table
Heats of formation and relative stabilities of the tautomeric forms of ethyl-4,4-dicyano-3-methyl-3-butenoate by AM1 calculations.
Tautomer | |||
−24,18846 | 0 | ||
−6,2391 | 17,94936 | ||
−8,38831 | 15,80015 | ||
3,558174 | 27,746634 | ||
−8,176637 | 16,011823 | ||
−8,175188 | 16,013272 | ||
17,81065 | 41,99911 | ||
17,98366 | 42,17212 |
The predicted most likely tautomerization process involves the conversion of the nitrile-keto form
The mass spectrum of ethyl-4,4-dicyano-3-methyl-3-butenoate is shown in Figure
Mass spectrum of ethyl-4,4-dicyano-3-methyl-3-butenoate.
From the assignment of the main fragment peaks it seems clear the occurrence of the ketenimine form because there exist fragment ions that can only be explained from that tautomer. The proposed fragmentation mechanisms are supported by the data although it should be noted that there is no absolute proof for them since there might be alternative pathways that are not eliminated by these experiments.
The peaks at m/z 104, 105, 106, 132, 133, and 150 can be justified from both tautomeric forms (Scheme
Fragment pathways involving both tautomeric forms of ethyl-4,4-dicyano-3-methyl-3-butenoate.
The fragment ion at m/z 66 can only be justified from the ketenimine form (Scheme
Fragmentation pathways involving ketenimine tautomers of ethyl-4,4-dicyano-3-methyl-3-butenoate.
It seems that the fragment at m/z 78 could be assigned to the ketenimine since the only possible alternative to form this ion would come from that one at m/z 106 by loss of HCNH through hydrogen rearrangement.
In case that tautomerization involving the enol from the ester moiety occurs, there are no evident pathways for the formation of m/z 66 and the ions in the range m/z 104–106.
The fragmentation pathways were confirmed by GC/MS-Ion Trap experiments (Table
MS2 data for ethyl-4,4-dicyano-3-methyl-3-butenoate.
Precursor ion (m/z) | Relevant product ions (m/z) |
---|---|
178 | 150, 133, 132, 106, 105, 104, 66 |
150 | 106, 78, 66 |
133 | 105 |
132 | 104 |
106 | 78, 66 |
Figure
Mass spectrum of diethyl-2-cyano-3-methyl-2-pentenodiate.
Scheme
Fragmentation pathways involving all tautomeric structures of diethyl-2-cyano-3-methyl-2-pentenodiate.
The ion at m/z 153 is not significant maybe due to the lower probability of the double hydrogen rearrangement.
The m/z 124 can be explained from the nitrile form (Scheme
Fragmentation pathway involving the nitrile form of diethyl-2-cyano-3-methyl-2-pentenodiate.
The fragment ion at m/z 67 can only be explained from the ketenimine form (Scheme
Fragmentation pathway involving the ketenimine form of diethyl-2-cyano-3-methyl-2-pentenodiate.
The following fragmentation pathways were confirmed by GC/MS-Ion Trap experiments (Table
MS2 data for diethyl-2-cyano-3-methyl-2-pentenodiate.
Precursor ion (m/z) | Relevant product ions (m/z) |
---|---|
180 | 152, 124 |
179 | 151, 134, 123, 107, 106 |
152 | 124 |
151 | 123, 107, 106, 97, 96 |
134 | 106 |
123 | 97, 96, 79, 69 |
107 | 79 |
In order to better support the specificity of the proposed fragmentation pathways, isotopic exchange with methanol-d1 was carried out for the ethyl-4,4-dicyano-3-methyl-3-butenoate. The corresponding mass spectrum is shown in Figure
Mass spectrum of ethyl-4,4-dicyano-3-methyl-3-butenoate after isotopic exchange with methanol-d1.
As observed, not only expected shifts are observed (m/z 66-67, m/z 78-79, m/z 104-105, m/z 105-106, m/z 106-107, m/z 132-133, m/z 133-134, m/z 150-151, m/z 178-179) but also m/z 68, m/z 80, m/z 108, m/z 135, m/z 152, and m/z 180 are present. This can be explained by taking into consideration the equilibria in Scheme
H/D isotopic exchange for ethyl-4,4-dicyano-3-methyl-3-butenoate
To get additional supporting evidence for the occurrence of the ketenimine tautomer that involves the free methyl group, the synthesis of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate was carried out. This product was analyzed not only by MS (Figure
Nuclear magnetic resonance spectra (1H and 13C) of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate.
(CDCl3) | |
(CDCl3) |
Mass spectrum of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate.
The ion at m/z 163 constitutes the base peak, and it seems to be only explainable from the ketenimine (Scheme
Proposed fragmentation pathway involving the ketenimine form of ethyl-4,4-dicyano-2,2-diethyl-3-methyl-3-butenoate.
GC/MS-Ion Trap experiments showed that this ion is generated directly from the molecular ion at m/z 234.
After isotopic exchange with methanol-d1 the fragment ion at m/z 163 shifts to m/z 164, that constitutes a supporting evidence for the proponed fragmentation pathway.
Ketenimines react with nucleophiles as amines and alcohols [
Reaction of ethyl-4,4-dicyano-3-methyl-3-butenoate with diethylamine involving the ketenimine Form.
Equimolar amounts of ethyl-4,4-dicyano-3-methyl-3-butenoate and diethyl amine in diethyl ether were mixed and allowed to react until detection of product formation. After recrystallization the reaction products were identified by 1H and 13C NMR (Table
Nuclear magnetic resonance spectra (1H and 13C) of the amination products of ethyl-4,4-dicyano-3-methyl-3-butenoate.
(CDCl3) | |
(CDCl3) |
The bidimensional NMR allowed to confirm the assignments (see experimental part). In addition, the preparation and detection of the amidines from the nitrile in neutral medium is also a strong indication of the presence of the ketenimine structures in the equilibrium.
The reported evidences found by mass spectrometry in regard to the occurrence of the nitrile-ketenimine tautomerism have been supported through isotopic exchange, MS2 and reactivity experiments (amination reaction and NMR determinations). AM1 calculations were consistent with the relative importance of the ketenimine tautomer for one of the compounds here studied. Although for a long time the value of mass spectrometry as a tool to predict the occurrence of prototropic interconversions in the gas phase has been questioned, nowadays there is enough experimental work that supports this approach. In this sense, there are some key aspects to keep in mind: there should be specific assignments of fragment ions to tautomeric structures, tautomerization is not supposed to proceed between ionic species, and this approach does not intend to constitute a quantitative tool.