Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
HNO3/HFIP: A Nitrating System for Arenes with Direct Observation of π‑Complex Intermediates Le Lu, Huixin Liu, and Ruimao Hua* Department of Chemistry, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: This report describes an efficient nitrating system for the nitration of arenes at room temperature by using an equivalent of nitric acid in HFIP (1,1,1,3,3,3-hexafluoroisopropanol). The π-complex intermediate of an arene with a nitronium ion stabilized by HFIP can be directly observed by UV−vis spectra and is supported by theoretical calculations.
T
experimental and computational UV−vis spectra. In this paper, we report the detailed results of our investigation. We first have to examine the stability of HFIP in the presence of HNO3, although the oxidation reaction of benzyl alcohols in HFIP using 68% HNO3 as the oxidant,3j and the formation of hexafluoroisopropyl nitrate under very harsh conditions from the reaction of HFIP with the excess amount of concentrated HNO3 (>90%) and oleum6 were known. The computational studies (see the Supporting Information (SI)) reveal that the dehydrating energy of protonated HFIP (78.8 kcal/mol) is about three times as high as that of 2propanol (25.2 kcal/mol), which mostly prevents its conversion into carbocation and further transformation. In addition, HFIP lacks β-H, which makes it impossible to produce alkenes via the second-order elimination. Moreover, no considerable amount of nitrated HFIP can be observed in a solution of concentrated HNO3 in HFIP (1.0 M) at 25 °C for 1 h, which is confirmed by 1 H NMR spectra (see SI). From the computational studies and experimental results, it has also been confirmed that HFIP is stable in the presence of concentrated HNO3. Then, we performed the nitration of arenes in HFIP at room temperature. The results of the nitration reaction of electron-rich and electron-deficient arenes at 25 °C with an equivalent of 68% HNO3 or concentrated HNO3 in HFIP (1.0 M) are summarized in Table 1. After 1 h, the mononitrated products were isolated in good to high yields, and the use of concentrated HNO3 resulted in a considerable increase of yields with almost the same ratios of the nitrated isomers. One of the most advantageous features of an HNO3/HFIP system is the fact that both benzene, electron-rich arenes (toluene, p-
he nitration of arenes is one of the most important and fundamental electrophilic aromatic substitutions (SEAr). It usually requires an excess amount of the mixed acid of nitric acid with concentrated sulfuric acid, resulting in a significant problem on workup by water washing before isolation of the product to produce a large amount of acidic wastewater. Therefore, a wide variety of catalytic systems have been developed with the use of 1 equiv of nitric acid to provide efficient and green nitration procedures.1 On the other hand, the solvent effect is somewhat observed in most organic synthetic reactions to affect the rate and outcomes of transformation.2 In particular, HFIP (1,1,1,3,3,3hexafluoroisopropanol) has been well applied and investigated as a unique solvent in organic synthesis,3 owing to its extreme properties, including strong hydrogen-bond donating ability, high ionizing and stabilizing ability, low viscosity, low boiling point, and recyclability. In addition, a combined computational and experimental analysis has revealed that the aggregation effect of HFIP is one of the critical factors to promote the reactions.4 Recently, the properties and applications of HFIP have been summarized in detail in a review paper.3l It would be apparently advantageous to develop the nitration system under mild conditions with the use of 1 equiv of HNO3 and without the use of catalysts or other promoters with simple workup from the point of view of economy and green chemistry. Therefore, in continuation of our interest in the development of a nitration reaction of arenes,5 and due to the extreme advantages of HFIP, we have investigated the nitration reaction of arenes in HFIP at room temperature using 1 equiv of HNO3 and have disclosed some interesting features: (1) the nitration process occurs smoothly with high efficiency of HNO3; (2) the π-complex intermediates of arenes with a nitronium ion can be stabilized by HFIP and confirmed by © XXXX American Chemical Society
Received: March 31, 2018
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DOI: 10.1021/acs.orglett.8b01028 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
indicate the reaction occurring rapidly, which was further supported by the GC−MS analysis of reaction mixture. In addition, as other advantages of the present nitration system, the solvent of HFIP (ca. 90%) can be recovered by simple distillation under reduced pressure after the nitration reactions with a 10 mL scale, and the mononitrated products were obtained by silica gel column chromatographic separation and were characterized by GC−MS and NMR spectra (see the SI). It is worth noting that the mentioned phenomena of color change of the nitration reaction could not be observed either when 68% HNO3 was used as a nitrating reagent or when other solvents, such as sulfolane, acetic acid, nitromethane, dichloromethane (DCM), or even trifluoroethanol (TFE), were employed with the use of 1 equiv of concentrated HNO3. Very recently, Galabov and Schaefer have investigated the formation of a π-complex intermediate between benzene and a nitronium ion in a mixed acid solution of nitric and sulfuric acid by theoretical calculations and UV−vis spectra of the reaction.8 On the basis of the reported results, one important piece of evidence to support the formation of a π-complex intermediate is to directly observe a broad band absorption at around 400 nm resulting from the electron excitation from the HOMO of arenes to the LUMO of nitronium cation by theoretical calculations without considering the interaction of a sulfuric acid molecule in a vacuum. The theoretical modeling concludes that the nitration reaction favors a stepwise mechanism with intermediate formation of the π- and σ-complexes. Since intense change in color of the solution indicates the formation and conversion of π-conjugated intermediates with strong UV−vis absorption, we propose that the formation and disappearance of the brown solution in the nitration of arenes with the use of an HNO3/HFIP system results from the formation of a π-complex and its further transformation. Therefore, we next attempted to verify the formation of a πcomplex intermediate by experimental and computational studies of UV−vis spectra in HFIP. Although there are several variations of the mechanism for the nitration of arenes, the commonly proposed mechanism involves the formation of a π-complex via the interaction of a nitronium cation (NO2+) species with the π-system of arene and then the formation of a σ-complex intermediate; finally, the nitrated product is obtained via removal of the ipso-proton, as shown in Scheme 1.9 In the present HNO3/HFIP system, without use of other acids, nitronium cation is considered to result from the autoprotolysis of nitric acid.
Table 1. Yield and Selectivity of Nitration in HFIP yieldb (%) a
entry
arene
1 2 3 4 5 6 7 8 9
benzene toluene p-xylene mesitylene durenec anisolec PhF PhCl PhBr
68% HNO3 80 75 85 88 90 82 56 81 86
(o/m/p = 48:3:49)
(o/p (o/p (o/p (o/p
= = = =
40:60) 18:82) 28:72) 30:70)
90% HNO3 90 99 96 92 95 90 85 88 93
(o/m/p = 48:2:50)
(o:p = 40:60) (o/p = 20:80) (o/p = 32:68) (o/p = 36:64)
a
Reactions were performed using 1.0 mmol of arenes and 1 equiv of nitric acid in 1.0 mL of HFIP at 25 °C for 1 h. bIsolated yield. cThe reaction was performed at 0 °C within 5 min.
xylene, mesitylene, durene, anisole), and electron-deficient arenes (PhF, PhCl)7 undergo the nitration reaction with concentrated HNO3 smoothly with high efficiency of HNO3 to give the nitrated products in high yields (85−99%). Although the isolated yields summarized in Table 1 were obtained after a 1 h reaction at 25 °C, one of the other features is an estimation method for the reaction progress, which can be visually appreciated by the color change of the reaction solution. As shown in Figure 1, the progress of the formation and
Figure 1. Color change of reaction mixture. The left of each picture shows the appearance of 1.0 mL of 1.0 M HFIP/HNO3 (90% HNO3) with a stir bar, and t = 0 min shows the initial state of reaction mixtures after arenes are added. In the case where durene was used, the colorless solution of the first photo is a solution of predissolved durene in HFIP, and then HNO3 is added in the second photo since durene cannot be dissolved immediately when it is added to HFIP.
Scheme 1. General Proposed Mechanism of Nitration of Arenes
disappearance of the brown colored solution after the addition of arenes was observed differently for each reaction bottle from minutes to hours, depending on the arenes used. The kinetic experiments of were also studied by using time-resolved UV− vis absorption spectroscopy, and the krel (kobs./ kobs.(benzene)) values of intermediate decay are consistent with the observed color-fading rate (see SI). In addition, an alternative experimental result has disclosed that durene also undergoes the nitration reaction with 1 equiv of concentrated HNO3 at 0 °C in HFIP, and the complete conversion can be confirmed by the color change of the solution from deep brown to light yellow within 1 min to
It has been found that the UV−vis absorption spectrum of the reaction mixture of benzene in HNO3/HFIP at 25 °C shows a broad shoulder at 427 nm (
