Condensation Reaction between Phenanthroline-5, 6-diones and

*E-mail: [email protected]. The synthetic route to obtain the pyrazino polypyridinic type of ligands generally involves a condensation reaction between a d...
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Chapter 6

Condensation Reaction between Phenanthroline-5,6-diones and Ethylenediamine and Its Optimization through Dialogue between Theory and Experiment Luis Sanhueza,1 Diego Cortés,1 Iván González,1,2 and Bárbara Loeb1,* 1Facultad

de Química, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago, Chile 2Facultad de Ciencias de la Salud, Universidad Central de Chile, Lord Cochrane 417, Santiago, Chile *E-mail: [email protected]

The synthetic route to obtain the pyrazino polypyridinic type of ligands generally involves a condensation reaction between a diaminne and a dione. In the case of pyrazino[2,3-f][1,10]phenanthroline, ppl, and pyrazino[2,3-f][4,7]phenanthroline, ppz, a notoriously lower yield for the condensation reaction of the later has been observed. In this work, experimental results along with DFT methods allowed us to elucidate and improve the synthetic pathways involved in these ligands. Intermediary molecules for the corresponding condensation of dione and ethylenediamine were detected. By a continuous dialogue between theory and experiments the limiting reaction step was established as the formation of a “non-aromatic” intermediate, which was shown to be the cause for the lower yield observed for ppz. This intermediate was theoretically and experimentally characterized, thereby permitting us to facilitate its conversion to the desired product and obtain close to quantitative yield for the reaction.

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Introduction The use of polypyridines as organic reactants and/or coordinating ligands in transition metal complexes has been widely investigated. These versatile aromatic compounds permit us to modify the structural and electronic properties of coordination complexes and use them in applications such as solar cells (1, 2), OLED (3, 4) and nonlinear optical devices (5). Among polypyridinic ligands, dipyrido[3,2-a:2′,3′-c]phenazine (dppz), has been widely studied since the early discovery of its behavior as a spectroscopic probe of [Ru(bpy)2dppz]2+ in DNA intercalation (6). The analogous ligand, pyrazino[2,3-f][1,10]- phenanthroline (ppl), has been less studied (7, 8). The synthesis of both of these ligands by condensation of the corresponding dione with ethylene diamine is straightforward (9).

It has been found that the use of the structural “isomers” of the aforementioned ligands, dipyrido[2,3-a:3′,2′-c]phenazine (dbq′), and pyrazino[2,3-f][4,7]phenanthroline, (ppz or dpp′), affect considerably the spectroscopic properties and the electronic behavior of coordination complexes of the type [Ru(R2-bpy)2(L)]2+, where L is dbq´ and ppz. For example, the absorption of [Ru(bpy)2(ppz)]2+ is noticeably red-shifted when compared to [Ru(bpy)2(ppl)]2+, while its lifetime is markedly enhanced (10, 11), making the compound promising for device applications. However, the main limitation for their use, particularly for ppz, involves overcoming the synthetic challenge. As mentioned above, ppl can be obtained by simple condensation between ethylenediamine and 1,10-phendione with more than 90% yield (12), but the synthesis of ppz under the same reaction conditions was reported to give significantly lower yields (13) (Scheme 1). It has been suggested that the low yield of this synthesis is due to a disproportionation reaction, obtaining an aromatic species (the desired product) and also a "non-aromatic" derivative, H2ppz (14). It should be mentioned that an alternative synthetic method gave ppz with good yield, but with a longer and more complex route involving potentially unstable or air-sensitive intermediates (14). In order to overcome the difference in behavior for the synthetic process, a continuous dialogue between theory and experiments was undertaken to evaluate the stages involved in the condensation reaction and the variables so as to control and improve this reaction. A separate analysis of the starting materials, the intermediate products, and the final products was undertaken, that as a whole permitted us to understand and control the reaction.

80 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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Scheme 1. Condensation reactions for ppl and ppz compounds under the same experimental conditions.

Analysis of Starting Materials As can be seen in Scheme 1, under similar experimental conditions, after 13 h stirring, ppl precipitates as a yellow pale solid and is obtained in 85 % yield, while in similar conditions ppz is obtained in 42 % yield. The yields are in agreement with previously reported results (12, 13). As a first stage looking for variables that could explain the difference in yield, an analysis in regard to the starting materials was considered. Specifically, the idea was to understand if the presence of the N groups in 4,7 positions affect the reactivity of the phendione when compared with 1,10 phendione. Conceptual density functional theory (DFT) was applied to evaluate the global and local reactivity properties. The global reactivity indexes, molecular hardness η (15) and electrophilicity ω (16), given in Table 1, show that 1,10-phendione and 4,7-phendione have almost the same electronic reactivity and electrophilic character. The differences of η and ω between 1-10-phendione and 4,7-phendione are negligible in this context (1.78 and 2.34 kcal/mol, espectively). Moreover, taking into account that condensation is a frontier molecular orbital-controlled step at local level, the Fukui Functions (FF) (17, 18) for susceptible sites to electrophilic (f+) and nucleophilic (f-) attacks were obtained by frozen core approximation. Results (Figure 1) show that no significant difference can be found; in both molecules the larger values of f+ and f are located on the C and O atoms that take part in the condensation step. FF by finite difference approximation using the Yang-Mortier scheme was also calculated, with analogous results. Therefore, according to the global and local indexes, a difference in reactivity of the phendione precursors seems not likely to be the reason for the difference in yields observed.

81 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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Table 1. Molecular hardness (η) and electrophilicity (ω) for 1,10 and 4,7 phendione precursors. Molecule

η (kcal/mol)

ω (kcal/mol)

1-10 phendione

41.49

193.84

4-7 phendione

39.71

191.50

Figure 1. Condensed Fukui Functions for electrophilic (f+) and nucleophilic (f-) attack calculated for 4,7-phendione and 1,10-phendione.

With these experimental and computational data, the complete reaction of phendione and ethylenediamine was divided in two steps: condensation between the oxygens of phendione and the NH2 groups of ethylenediamine, and aromatization reaction to generate the respective ppl and ppz aromatic-type compounds.

82 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

If the second step involving an aromatization (oxidation) reaction is the ratelimiting step, the presence of O2 should have a role to obtain the desired aromatic product. Therefore, the same previous reactions were repeated under identical conditions as in Scheme 1, but under N2 atmosphere. After 17 hours stirring, no precipitation was observed, and the solutions for both reactions kept their deep red color. The solvent of these reddish solutions was eliminated by evaporation, and the corresponding red-to-orange solids isolated. It was assumed that the solids correspond to the “non-aromatic” intermediates for ppl and ppz respectively.

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Analysis of Intermediates In order to prove this assumption, a complete analysis of these products was done. The influence of these intermediates on the difference in reaction yield was additionally analyzed. UV-Vis Spectra A comparison of the absorption spectra between the “non-aromatic” intermediates (isolated by the reaction in N2 atmosphere) and the corresponding final products was conducted. The first spectra show mainly a red-shifted transition at 284 nm and 257 nm, displaced by 32 nm and 5 nm respectively for “non-aromatic” ppz and ppl from the related aromatic compound, where all transitions are the π → π * type. Moreover, new bands appearing at 376 and 398 nm can be observed for ppl and ppz intermediates respectively. In contrast, the final products are completely transparent in this region. Two different structures for each intermediate are feasible, differing in the protonation of the pyrazinic N, as shown in Scheme 2.

Scheme 2. Possible structures for the non-aromatic intermediates. In order to determine the most probable intermediate, experimental and theoretical absorption spectra for both intermediates were compared, and are shown in Figure 2. For this analysis, the goal is to determine if the pyrazinic 83 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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nitrogens of the intermediates are protonated, i.e., to understand if the N is of sp3(A) or sp2(B) type.

Figure 2. Experimental and calculated absorption spectra in MeCN for the “A proposed intermediates” (with C and N sp3 configuration). i) ppl and ii) ppz compounds. When comparing theoretical and experimental UV-Vis spectra for the “A” type intermediates (scheme 2), i.e., with N protonated, the same tendency is observed for the ppl and the ppz derivatives. For ppl intermediates, good correlation can be observed from 270 to 400 nm, where intensities and absorption positions are well simulated. This correlation is quite clear for the 276 nm and 298 nm bands. In addition, the calculation for this “A” type structure predicts a band at 363 nm, with a difference of 0.12 eV compared to the experimental band, at 376 84 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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nm (Figure 2-A). In the case of the “A” type intermediate for ppz, the same good correlation between experimental and theoretical information is observed (Figure 2-B). Specifically, the transitions at 285 nm and 233 nm correlate perfectly well. Regarding the lower energy band for this intermediate, a difference of 0.19 eV is observed between the experimental (398 nm) and theoretical (425 nm) bands. Although greater than that of the ppl derivative, it is still in an acceptable range. Regarding the “B” type structure for the ppz intermediate, the theoretical calculations determine a relatively intense band at 262 nm that is absent in the experimental spectra. Moreover, the calculation for the lower energy band, although closer to the experimental value, appears with a negligible oscillator strength (4,81x10-3) compared to 0.081 for A-ppz. According to the previous analysis, the intermediate structure type “A” seems to be the more probable. NMR characterization sheds more light about this assumption. NMR Characterization The four compounds: ppl, ppz, and the corresponding experimental intermediates were fully characterized by 1H-NMR spectroscopy. Twodimensional measurements were carried out when necessary. For ppl and ppz products the positions and couplings were in agreement with previously reported characterizations (7–10) (Scheme 3 and Table 2). In order to corroborate the nature (A or B) of the intermediates, the experimental products were also fully characterized (Table 2).

Table 2. 1H-NMR characterization for ppl and ppz compounds and their corresponding intermediates

a

Moleculea

Ha

Hb

Hc

Hd

NH

ppla

9.22

7.92

9.43

9.13

--

ppza

8.94

7.83

9.27

9.25

--

ppl-intermediateb

8.15

7.48

8.91

3.43

--

ppz-intermediateb

8.30

7.07

8.29

3.48

4.89

In CDCl3.

b

In CD3OD.

13C

DEPT spectra in deuterated methanol for the ppl reaction intermediate shows a strong signal at 45.02 ppm that is unequivocally assigned to CH2 (Figure 3). On the contrary, for the ppz intermediates, only a trace of a possible aromatic impurity can be observed in this region. Additionally, for the ppz reaction intermediates, HSQC and HMBC NMR spectra in MeOD were measured. They showed the coupling between H-d(3,48 ppm) and C-7 at 41,71 ppm to be direct, and the same proton with C-6 126,79 at ppm, confirming that proton signal at 3.48 ppm corresponds effectively to CH2 from the saturated fragment in the molecule, where carbons are of the sp3 type. 85 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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Scheme 3. NMR characterization for ppl and ppz compounds, same labels can be used for intermediates.

Figure 3. NMR DEPT spectra in deuterated methanol for the intermediates for ppl (upper plot) and ppz (lower plot) 1H-NMR

spectrum in DMSO-d6 of the ppz-intermediate shows a signal at 3.54 ppm, attributable to the aliphatic “d” protons. Additionally, a signal at 6.14 ppm appears. According to HSQC spectrum, this signal is not related to a C atom, indicating indirectly that this H should therefore be coordinated to a N atom. This conclusion was supported by HMBC spectroscopy, where a coupling between H and C4 (quaternary) at 139.2 ppm was observed, confirming the presence of a direct NH bond after condensation and therefore an “A” type structure. 86 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

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In order to check the solvent effect in the condensation reaction, the synthesis for ppl and ppz was repeated in the same conditions as in Scheme 1, but in dry CDCl3. Effectively, for both ppl and ppz, after 4 h no product and/or red solution was observed. The same was observed when CHCl3 and THF were used. These results reflect the nature of the solvent used, which is quite important for the condensation reaction, with a protic solvent needed for the reaction to occur. Moreover, in aprotic solvents, after ending the reaction, the starting materials can be observed by NMR analysis, without any change. The keto-enol tautomerism is well known for this type of systems (19), and the protic solvent could be playing an important role in it. This tautomerism would occur before the nucleophilic attack involved in the condensation reaction.

Theoretical Reactivity Indexes To understand the preference of an “A” type structure, and specially to answer the original question about the reasons of a low yield in the ppz synthesis compared to ppl, we returned to theoretical calculations, checking local reactivity properties for each “non-aromatic” compound. The same global reactivity indices were determined for the four intermediaries (Table 3).

Table 3. Molecular hardness (η) and electrophilicity (ω) for non-aromatic intermediates and products Molecule

η (kcal/mol)

ω (kcal/mol)

A-ppl-intermediate

45.57

70.07

A-ppz-intermediate

36.53

71.35

B-ppl-intermediate

43.98

134.58

B-ppz-intermediate

43.20

128.57

The η index of electronic reactivity is similar between non-aromatic intermediaries, with a difference of ~7 kcal/mol. However, ω for “A-type intermediates” is less than for “B-type” ones by ~60 kcal/mol; this difference would make them preferable candidates for the aromatization to ppl and ppz by oxidation because A-ppl-intermediate and A-ppz-intermediate are better nucleophiles than B-ppl-intermediate and B-ppz-intermediate. Regarding the reason for the difference in yields of both reactions, the second step of the synthesis, i.e., the oxidation of the intermediate to generate the final product, was analyzed. The total energy for the intermediate compounds was determined; A-ppz-intermediate is ~30 kcal/mol more stable than the A-ppl-intermediate. This can be caused by the interaction between the hydrogen atoms of the NH groups with the nitrogen atoms in “Y” position of A-ppz-intermediate, establishing a higher energetic barrier to form the final product with respect to A-ppl-intermediate. In addition, the susceptible oxidation sites through an 87 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

electrophilic attack of the intermediaries were analyzed. This is a process controlled by the frontier molecular orbitals. However, in terms of the local reactivity, it is not possible to find significant differences because in aromatic and non-aromatic compounds the sites with larger contribution to f- are on the nitrogen atoms adjacent to the CH2 groups.

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Complete Conversion of Products The analysis described so far shows that the lower yield in the condensation reaction to obtain ppz is not attributable to the reactivity of the starting material. The reason seems to be related to the properties of the intermediate product, identified as an “A” type ppz-structure. Theoretical calculations show that the A-ppz-intermediate has a lower tendency to donate electrons than the A-ppl-intermediate. As mentioned above, the electronic pairs from the N atoms in 4 and 7 positions interact with NH from the piracinic group, hindering the aromatization into the ppz compound. Therefore, it can be thought that the strength of the oxidant is important, and that it should have the capacity to aromatizate the corresponding intermediate. In the case of the A-ppz-intermediate, a stronger oxidant than oxygen from air would be needed, avoiding at the same time decomposition. To test this assumption, the same reaction to obtain ppz shown in Scheme 1 was carried out, but adding MnO2. Specifically, 8 eq. of this oxidant were added to the mixture and the solution stirred for additional 2 hours. The reaction was followed by UV-Vis spectroscopy until the disappearance of the 398 nm band, characteristic of the intermediate. The product was precipitated by addition of an excess of diethyl ether. The 1H-NMR spectrum of this product corresponded to ppz, with no evidence of any by-product. The reaction yield was close to be quantitative. Elemental analysis gave also satisfactory results.

Conclusion The analysis of all previous experimental and theoretical data showed that the low yield for the condensation reaction to obtain ppz cannot be attributed to the corresponding starting material, but rather to the nature of the non-aromatic intermediate. Through identification of its structure and local reactivity analysis, the need of a different oxidant was revealed and applied. To our knowledge, this is the first time this simple condensation reaction could be conducted for ppz in close to quantitative yield. This was possible by a dynamic dialogue methodology between theory and experiments that allowed us to identify, characterize and isolate the relevant intermediaries, and to optimize the reaction to achieve the product in almost quantitative yield.

Acknowledgments This work was financially supported by FONDECYT Chile by Project Nº 1110991. The authors gratefully acknowledge Dr. Enrique Castro and Dr. David Moreno for helpful discussions. 88 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

To the memory of Dr. Ernest Eliel, for the long hours of interesting discussions during my visits to Chapel Hill, regarding scientific policies and the way to increase the development of chemistry in latin american countries. Definitely, they changed my way to conduct my academic career.

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