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Synthesis 2023; 55(02): 354-358
DOI: 10.1055/s-0041-1737327
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Special Issue dedicated to Prof. Alain Krief

Elucidation of the Nucleophilic Potential of Diazocyclopentadiene

Manfred Hartnagel
,
Armin R. Ofial
,
Herbert Mayr  ∗

Financial support of this work by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie is gratefully acknowledged.
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Dedicated to Professor Alain Krief on the occasion of his 80th birthday

Abstract

Diazocyclopentadiene reacts with benzhydrylium ions (Ar2CH+) to give 2,5-dibenzhydryl-substituted diazocyclopentadienes. The kinetics have been determined photometrically in dichloromethane under pseudo-first-order conditions using diazocyclopentadiene in excess. Plots of the second-order rate constants (log k 2) versus the electrophilicity parameters E of the benzhydrylium ions gave the nucleo­philicity parameter N = 4.84 and susceptibility s N = 1.06 for diazo­cyclopentadiene according to the correlation log k(20 °C) = s N(E + N). Diazocyclopentadiene thus has a similar nucleophilic reactivity as pyrrole. Previously reported electrophilic substitutions of diazocyclopentadiene are rationalized by these parameters and new reaction possibilities are predicted.


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Key words

diazo compounds - kinetics - linear free energy relationships - nucleophilicity - reactivity scales

Diazocyclopentadiene (1), first synthesized by Doering and DePuy in 1953,[1] is characterized by a unique π-system. By attracting electrons from the N2 unit, the five-membered carbocycle adopts aromatic character (Figure [1]), which has been the topic of numerous theoretical[2] [3] [4] [5] [6] [7] [8] and spectroscopic investigations.[6] , [9–12]

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Figure 1Illustration of the aromatic character of diazocyclopentadiene (1)

In contrast to ordinary diazoalkanes, diazocyclopentadiene (1) is not attacked at C-1 by electrophiles, but at C–H positions, preferentially at C-2, thus giving rise to electrophilic aromatic substitutions. In 1963, Cram and Partos reported several electrophilic aromatic substitutions of 1,[13] for example, nitration to occur at C-2 and C-3, azo coupling with benzenediazonium ion at C-2, bromination with N-bromosuccinimide to give tetrabromodiazocyclopentadiene,[14] and mercuration with Hg(OAc)2 at C-2 and C-5. While 1 underwent a [π8s + π2s] cycloaddition with dimethyl acetylenedicarboxylate, electrophilic substitution at C-2 occurred with tetracyanoethylene.[13]

Photolysis of 1 has been reported to yield cyclopentadienylidene[15] [16] [17] [18] [19] and the insertion of 1 in transition metal–halogen bonds, a widely used method for the generation of many cyclopentadienyl complexes,[20] has been discovered by Reimer and Shaver.[21] In recent years, the interaction of 1 with the ethylene receptor in plants found great attention.[22] [23] In view of these numerous applications, it is surprising that the initial studies by Cram and Partos[13] on electrophilic substitutions of 1 have not been further developed.

We now report on the application of the benzhydrylium methodology[24] [25] [26] [27] [28] for quantifying the nucleophilic reactivity of 1 in order to elucidate the scope of potential electrophilic reaction partners. In previous work, we have demonstrated that Equation 1 can be used to calculate the rate constants of the reactions of electrophiles with nucleophiles from the electrophilicity parameter E and the solvent-dependent nucleophile-specific parameters N and s N.[24] [25] [26] [27] [28]

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Equation 1Linear free energy relationship for electrophile-nucleophile reactions

The benzhydrylium ions 2 used for the characterization of 1 and their electrophilicity parameters E are shown in Figure [2].

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Figure 2 Benzhydrylium ions 2 and their electrophilicity parameters E (from ref 26)

Combination of the benzhydrylium tetrafluoroborates 2a-BF4 and 2c-BF4 with 3 equivalents of diazocyclopentadiene 1 in dichloromethane gave high yields of the diazo-bis(diarylmethyl)cyclopentadienes 4a and 4c, respectively (Scheme [1]). The exclusive formation of the 2:1-products 4 shows that the cyclopentadiene ring in the intermediate monosubstitution products 3a and 3c is so strongly activated by the diarylmethyl group that 3a,c immediately undergo subsequent reactions with the benzhydrylium ions, even though 1 was used in excess. Analogously, the monosubstitution product 3b was not isolable when the benzhydryl acetate 2b-OAc was treated with zinc chloride etherate and 2 equivalents of diazocyclopentadiene 1. Due to the presence of two centers of chirality, the 2:1-product 4b was formed as a mixture of diastereomers, like the analogous bis-substitution product 4c.

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Scheme 1Products of the reactions of diazocyclopentadiene (1) with benzhydrylium ions 2 in dichloromethane

Obviously, the activating effect of the dianisylmethyl group in 3e was weaker than that of the other diarylmethyl groups, because the reaction of dianisyl-chloromethane 2e-Cl with ZnCl2·OEt2 and diazocyclopentadiene (1) gave a mixture of the mono- and disubstituted products 3e and 4e, respectively, which was separated by chromatography (Scheme [1]).

The kinetics of the reactions of 1 with the benzhydrylium ions 2 were measured photometrically by following the decays of the absorbances of the benzhydrylium ions in the presence of more than 10 equivalents of 1 (pseudo-first-order­ conditions). From the monoexponential decays of the benzhydrylium ion concentrations one can derive that under the conditions of the kinetic experiments, the formation of the 2:1-products 4 does not play a significant role. If this were the case, an increase of the rate with increasing conversion should be observable as the concentration of the more reactive 1:1-substitution product 3 grows during the reaction.

Table [1] lists the second-order rate constants that were either determined at 20 °C (as for the reaction of 1 + 2a) or extrapolated to 20 °C by using the Eyring equation and second-order rate constants from kinetic measurements at lower temperature. Details of the individual kinetic measurements are given in the Supporting Information.

Table 1 Rate Constants and Eyring Activation Parameters for the Reactions of Diazocyclopentadiene (1) with Benzhydrylium Ions 2 in Dichloromethane

ArAr′CH+

k(20 °C) (M–1 s–1)

ΔH ‡ (kJ mol–1)

ΔS ‡ (J mol–1 K–1)

2a

3.45 × 10–3

2b

288

37.5 ± 1.4

–69.7 ± 6.2

2c

320

35.1 ± 0.8

–77.2 ± 3.6

2d

1.94 × 103

24.5 ± 0.1

–98.2 ± 0.7

The negative activation entropies in Table [1] are in the typical range for bimolecular reactions and similar to those for the reactions of benzhydrylium ions with other diazo­alkanes.[29]

As shown in Figure [3], the correlation of log k versus electrophilicity E has an intercept of –4.84 on the abscissa, which corresponds to the nucleophilicity parameter N = +4.84 for 1, and the slope of s N = 1.06 is comparable to those for pyrroles and furans.[30] [31]

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Figure 3 Plot of log k(20 °C) for the reactions of diazocyclopentadiene (1) with benzhydrylium ions 2 in dichloromethane (Table [1]) vs the electrophilicity parameters E of the benzhydrylium ions 2 (Figure [2])

The nucleophilicity parameter N = 4.84 derived from Figure [3] allows one to compare the nucleophilicity of 1 with those of cyclopentadiene and structurally related heteroarenes. According to Figure [4,] 1 is significantly more nucleophilic than thiophene and furan and their 2-methyl-substituted derivatives, comparable to pyrrole and N-methylpyrrole. For that reason, one can expect electrophiles, which are known to react with pyrrole,[30] also to react with diazocyclopentadiene (1).

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Figure 4Comparison of the nucleophilic reactivities of 1 with those of cyclopentadiene and structurally related heteroarenes and potential electrophilic reaction partners (from ref. 31)

Suitable electrophilic reaction partners of 1 may also be identified by our rule of thumb[26] that reactions of electrophiles with nucleophiles can be expected to take place at room temperature when E + N > –5. Figure [4] arranges electrophiles and nucleophiles in a way that compounds at the same level (E + N = –5) are expected to react slowly at 20 °C. Thus, diazocyclopentadiene (1) is predicted to react with all electrophiles positioned below it at room temperature. Only few reports in the literature allow one to examine this prediction.

Eitel and Wessely isolated 18% of 6 (Scheme [2]) when equimolar amounts of 1 and benzylidene-Meldrum’s acid 5 were kept in THF solution for 4 days in an ice-box (‘Eiskasten’, probably 0 °C).[32] With E = –9.15,[33] 5 is a rather strong Michael acceptor and, therefore, can undergo electrophilic aromatic substitutions with 1. There are only few neutral electrophiles, which can attack 1 with formation of only one new bond. Weaker Michael acceptors might undergo concerted cycloadditions with 1, however, as previously reported for the reactions of alkynes with 1 and further substituted diazocyclopentadienes.[13] [34]

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Scheme 2 Reaction of diazocyclopentadiene (1) with benzylidene Meldrum’s acid 5 (as described in ref. 32)

Hafner and associates[35] have systematically investigated the reactions of 1 with donor- and acceptor-substituted benzenediazonium ions 7 and found exclusive C-2-attack, in line with Cram’s report.[13] While azo-compounds 8 derived from acceptor-substituted benzenediazonium ions were stable, those derived from donor-substituted benzenediazonium ions underwent 10π-cyclization with formation of cyclopenta-annulated 1,2,3,4-tetrazines 9 (Scheme [3]).[35]

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Scheme 3Azo couplings of 1 with benzenediazonium ions 7 (as reported in ref. 35)

While there is a limited number of neutral electrophiles of E > –10,[31] which can be expected to undergo non-catalyzed reactions with 1, stabilized carbocations are probably the most versatile group of reaction partners of 1. To our knowledge reactions with iminium ions have not yet been reported, though Figure [4] predicts imidazolidinone-derived iminium ions to react fast with 1.[36] Also the less electrophilic pyrrolidine-derived iminium ions with E > –10 can be expected to be suitable reaction partners of 1.[37]

Substrates suitable for organocatalytic reactions via iminium ions must be nucleophilic enough to react with the intermediate iminium ions, but not too nucleophilic to avoid background reactions with the carbonyl precursors of the iminium ions.[38] Diazocyclopentadiene (1) with N = 4.84 fulfils this criterion. The resulting suggestion to employ 1 as substrate for iminium-activated reactions is supported by MacMillan’s report on imidazolidinone-catalyzed reactions of unsaturated aldehydes with pyrroles,[39] since Figure [4] shows that pyrroles have a similar nucleophilicity as 1.

NMR spectra were acquired with a Bruker WM 300 spectrometer. 1H NMR spectra (300 MHz) refer to CDCl3 (δH = 7.24). 13C NMR spectra (75.5 MHz) were calibrated to CDCl3 (δC = 77.00). DEPT experiments were used to obtain information about the multiplicity of 13C resonances. IR spectra were recorded on a PerkinElmer Spectrophotometer 197. Mass spectra were obtained on a Varian 311A instrument. Microanalyses were carried out on a PerkinElmer 240 apparatus.

Diazocyclopentadiene (1) was obtained in 62% yield by diazo group transfer from p-tosyl azide to cyclopentadiene using diethylamine as the base[40] (procedure b). Benzhydrylium compounds 2a–e-X were synthesized as described previously.[27] [41] ZnCl2·OEt2 was prepared as reported.[42] CH2Cl2 was freshly distilled from CaH2 prior to use.


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Reaction of Diazocyclopentadiene (1) with Bis(4-dimethylaminophenyl)methylium Tetrafluoroborate (2a-BF4)

A solution of diazocyclopentadiene (1; 130 mg, 1.41 mmol) in CH2Cl2 (5 mL) was added to a solution of 2a-BF4 (160 mg, 0.470 mmol) in CH2Cl2 at rt. After stirring for 24 h in the dark, the mixture was hydrolyzed with concd aq ammonia (20 mL). The layers were separated, the aqueous phase was extracted with CH2Cl2 (2 × 20 mL), and the combined organic phases were dried (MgSO4). Evaporation of the solvent in vacuo and chromatographic purification over neutral Al2O3 (hexane/EtOAc 3:1) afforded 4a as dark-yellow crystals; yield: 130 mg (93%); mp 131–137 °C (dec.) (hexane).

IR (KBr): 3010, 2080, 1605, 1505, 1210, 745, 665 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 2.90 [s, 24 H, 4 × N(CH3)2], 5.14 (s, 2 H, Ar2CH), 5.35 (s, 2 H, 3-H), 6.64 and 7.05 (AA′BB′ system with J AB = 8.6 Hz, 16 H, ArH).

13C NMR (CDCl3, 75.5 MHz): δ = 40.7 [N(CH3)2], 49.0 (Ar2 CH), 72.7 (C=N2), 112.5 (C m ), 117.0 (C-3), 129.2 (C o ), 132.0 (C ipso ), 137.6 (C-2), 149.0 (C p ).

Anal. Calcd for C39H44N6 (596.8): C, 78.49; H, 7.43; N, 14.08. Found: C, 78.16; H, 7.49; N 13.18.


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Reaction of Diazocyclopentadiene (1) with Acetoxyferrocenyl-(4-methoxyphenyl)methane (2b-OAc)

Compound 2b-OAc (364 mg, 1.00 mmol) was dissolved in anhyd CH2Cl­2 (40 mL) and cooled at –78 °C under N2. ZnCl2·OEt2 (1 mL) and diazocyclopentadiene (1; 184 mg, 2.00 mmol) were added subsequently. The solution was kept for 1 h at –78 °C, then stirred with concd aq ammonia (40 mL). The layers were separated, the aqueous phase was extracted with CH2Cl2 (2 × 20 mL), and the combined organic phases were dried (MgSO4). Evaporation of the solvent in vacuo and chromatographic purification over neutral Al2O3 (hexane/EtOAc 20:1) afforded 4b as a brown oil with d.r. = 3:2; yield: 140 mg (40%).

1H NMR (CDCl3, 300 MHz): δ = 3.71–4.18 (m, 48 H, fc-H and OCH3), 4.85 and 4.90 (2 s, 2 × 2 H, Ar2CH), 5.45 and 5.51 (2 s, 2 × 2 H, 3-H), 6.78–6.83 (m, 2 × 4 H, ArH), 7.08–7.14 (m, 2 × 4 H, ArH); not all NMR signals of the two diastereomers are separated.

13C NMR (CDCl3, 75.5 MHz): δ = 44.64 (Ar2 CH), 55.15 (OCH3), 67.17, 67.23, 67.39, 68.18, 68.26, 68.42, 68.53 (7 × fc-CH), 71.98 and 72.15 (C=N2), 91.57 and 91.66 (fc-Cq), 113.23 and 113.30 (C m ), 116.00 and 116.06 (C-3), 129.45 and 129.50 (C o ), 135.47 and 137.07 (C-2 and C ipso ), 157.99 and 158.03 (C p ); not all NMR signals of the two diastereomers are separated.


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Reaction of Diazocyclopentadiene (1) with Ferrocenylphenyl­methylium Tetrafluoroborate (2c-BF4)

Using the same procedure as described for 2a-BF4, the reaction of 2c-BF4 (362 mg, 1.00 mmol) with 1 (276 mg, 3.00 mmol) gave 4c as a light-brown amorphous solid with d.r. = 1 :1; yield: 260 mg (81%).

1H NMR (CDCl3, 300 MHz): δ = 3.85–3.88 (m, 4 H, fc-H), 3.93 and 3.95 (2 s, 2 × 10 H, fc-H), 4.04–4.16 (m, 12 H, fc-H), 4.89 and 4.94 (2 s, 2 × 2 H, fcPhCH), 5.48 and 5.54 (2 s, 2 × 2 H, 3-H), 7.16–7.30 (m, 20 H, 2 × 2 C6H5).

13C NMR (CDCl3, 75.5 MHz): δ = 45.51 and 45.56 (fcPhCH), 67.30, 67.37, 67.44, 68.22, 68.29, 68.58, 68.63 (7 × fc-CH), 72.16 and 73.32 (C=N2), 91.09 and 91.19 (fc-Cq), 116.26 and 116.31 (C-3), 126.46 (C p ), 127.97, 128.04, 128.55, 128.59 (2 × C o , 2 × C m ), 136.69 and 136.75 (C-2), 143.15 (C ipso ); not all signals of the two diastereomers are separated.

Anal. Calcd for C39H32Fe2N2 (640.4): C, 73.15; H, 5.05; N, 4.37. Found: C, 73.12; H, 4.97; N, 4.21.


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Reaction of Diazocyclopentadiene (1) with Chlorobis(4-methoxyphenyl)methane (2e-Cl)

Diarylchloromethane 2e-Cl (263 mg, 1.00 mmol) was dissolved in anhyd CH2Cl2 (40 mL) and cooled to –78 °C under N2. ZnCl2·OEt2 (1 mL) and diazocyclopentadiene (1; 212 mg, 2.30 mmol) were added subsequently. The solution was kept for 1 h at –78 °C, then stirred with concd aq ammonia (40 mL). The layers were separated, the aqueous phase was extracted with CH2Cl2 (2 × 20 mL), and the combined organic phases were dried (MgSO4). Evaporation of the solvent in vacuo and chromatographic purification over neutral Al2O3 (hexane/EtOAc 20:1) afforded two products.


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Fraction 1, 3e

Yield: 120 mg (38%); yellow amorphous solid.

IR (KBr): 3020, 2400, 2080, 1610, 1505, 1470, 1290, 1245, 1210, 1175, 1030, 740, 665 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.76 (s, 6 H, 2 × OCH3), 5.32 (s, 1 H, Ar2CH), 5.52 (m, 1 H, 3-H), 5.88 (m, 1 H, 4-H), 6.68 (m, 1 H, 5-H), 6.83 and 7.11 (AA′BB′ system with J AB = 8.7 Hz, 8 H, ArH).

13C NMR (CDCl3, 75.5 MHz): δ = 49.2 (Ar2 CH), 55.1 (OCH3), 72.4 (C=N2), 113.7 (C m ), 116.9, 118.1, 119.0 (C-3, C-4, C-5), 129.6 (C o ), 135.3 (C ipso ), 137.9 (C-2), 158.2 (C p ).

MS (70 eV): m/z (%) = 318 (100, [M+]), 290 (25), 275 (42), 259 (39), 247 (13), 227 (13), 215 (27), 202 (21), 182 (12), 145 (10), 139 (13).

Anal. Calcd for C20H18N2O2 (318.4): C, 75.45; H, 5.70; N, 8.80. Found: C, 75.65; H, 5.78; N, 8.30.


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Fraction 2, 4e

Yield: 85 mg (31%); yellow amorphous solid.

IR (KBr): 2250, 2080, 1605, 1505, 1460, 1300, 1245, 1175, 1030, 900, 725, 645 cm–1.

1H NMR (CDCl3, 300 MHz): δ = 3.76 (s, 12 H, 4 × OCH3), 5.22 (s, 2 H, 2 × Ar2CH), 5.32 (s, 2 H, 3-H), 6.81 and 7.07 (AA′BB′ system with J AB = 8.7 Hz, 16 H, ArH).

13C NMR (CDCl3, 75.5 MHz): δ = 49.2 (Ar2 CH), 55.2 (OCH3), 72.7 (C=N2), 113.7 (C m ), 117.4 (C-3), 129.6 (C o ), 135.3 (C ipso ), 136.9 (C-2), 158.1 (C p ).

MS (70 eV): m/z (%) = 544 (0.1, [M+]), 516 (38), 409 (8), 395 (8), 227 (100), 121 (11).


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Kinetics

The reactions of the reference electrophiles with diazocyclopentadiene (1) were followed by photometry and evaluated with equipment as described before.[43] The CH2Cl2 used for the kinetic measurements was freshly distilled from CaH2 under dry N2.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Dr. Holger Schimmel for experimental assistance.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0041-1737327.
  • Supporting Information

CorrespondingAuthor

Herbert Mayr
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstr. 5-13, 81377 München
Germany   

Publication History

Received: 12 November 2021

Accepted: 17 November 2021

Article published online:
05 January 2022

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Zoom Image
Figure 1Illustration of the aromatic character of diazocyclopentadiene (1)
Zoom Image
Equation 1Linear free energy relationship for electrophile-nucleophile reactions
Zoom Image
Figure 2 Benzhydrylium ions 2 and their electrophilicity parameters E (from ref 26)
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Scheme 1Products of the reactions of diazocyclopentadiene (1) with benzhydrylium ions 2 in dichloromethane
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Figure 3 Plot of log k(20 °C) for the reactions of diazocyclopentadiene (1) with benzhydrylium ions 2 in dichloromethane (Table [1]) vs the electrophilicity parameters E of the benzhydrylium ions 2 (Figure [2])
Zoom Image
Figure 4Comparison of the nucleophilic reactivities of 1 with those of cyclopentadiene and structurally related heteroarenes and potential electrophilic reaction partners (from ref. 31)
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Scheme 2 Reaction of diazocyclopentadiene (1) with benzylidene Meldrum’s acid 5 (as described in ref. 32)
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Scheme 3Azo couplings of 1 with benzenediazonium ions 7 (as reported in ref. 35)