Download PDF
Synlett 2023; 34(10): 1153-1158
DOI: 10.1055/a-1951-2833
cluster
Dispersion Effects

Investigation of Alkyl–Aryl Interactions Using the Azobenzene Switch – The Influence of the Electronic Nature of Aromatic London Dispersion Donors

Dominic Schatz‡
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
,
Anne Kunz‡
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
,
Aileen R. Raab
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
,
Hermann A. Wegner∗
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
› Author Affiliations

This project was partially funded by the Deutsche Forschungsgemeinschaft (DFG, WE5601/8-1).
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Herein we report the synthesis of nonsymmetrically substituted azobenzene derivatives with meta-alkyl substituents on one side and meta-aryl moieties with electron-donating or electron-withdrawing groups on the other side. The half-lives for the thermal (Z)- to (E)-isomerization of these molecules were measured in n-octane, which allows investigation of the strength of the aryl–alkyl interactions between their substituents. It was found that the London dispersion donor strength of the alkyl substrate is the decisive factor in the observed stabilization, whereas the electronic structure of the aryl fragment does not influence the isomerization in a significant way.


#

Key words

London dispersion - azobenzenes - kinetics - molecular switches - CH–π interactions

One important parameter for the geometry and conformation of molecules are inter- and intramolecular noncovalent interactions. In this regard, the van der Waals force describes repulsive interactions, often referred to as steric hindrance, and an attractive part including dipole–dipole, dipole-induced dipole, as well as London dispersion forces.[1] In recent years the decisive role of these relatively small stabilizing interactions has been demonstrated by, for example, enabling long C–C bonds in adamantly dimers,[2] stabilizing DNA helices,[3] or aiding in the aggregation of rhodium complexes.[4] Stabilizing interactions can arise between polarizable surfaces that are in close proximity to each other, usually between 2.5–5 Å, allowing alkyl–alkyl, alkyl–aryl, and aryl–aryl interactions (or combinations of those) to influence the three-dimensional structure of compounds.[5] [6] [7]

As a single dispersive interaction is small from an energetically viewpoint, but grows with the number of interactions between atoms, they need to be viewed as a holistic system.[8] The small contribution to stability of a single interaction makes quantifying London dispersion forces challenging. In recent years, a variety of different molecular balances were introduced to allow measuring and comparing such small interactions. These balances are usually based on a thermodynamic equilibrium of a substrate, in which the ratio of two conformers or an equilibrium between an aggregated and nonaggregated state can be precisely measured. By placing a substituent at a position, which can engage in interactions in only one conformer or state, stabilizing effects can be observed by a change in the equilibrium. By precise construction of such a molecular balance, alkyl–aryl,[9] alkyl–alkyl,[10] [11] aryl–aryl,[12] as well as competing interactions with solvent molecules were studied.[11,13,14] The effects of London dispersion are an extensively studied field, and there have been a number of comprehensive reviews in recent years, indicating the importance of noncovalent interactions.[14] [15] Stabilizing interactions with aromatic scaffolds have also been extensively explored.[16] The N-arylimide balance, established by Shimizu, was used for observing the effect of face-to-face aryl, halogen–aryl, OH–aryl, n-aryl, as well as CH–aryl interactions.[17] [18]

We established a different molecular system that allows quantification of intramolecular forces based on the azobenzenes (AB) switch. Unlike the previous described balances, AB does not exist in an equilibrium of energetically close conformers but can be switched photochemically to a metastable (Z)-state. Upon isomerization, the end-to-end distance decreases drastically (from 9.1 Å to 6.2 Å at the para position)[19] allowing substituents at the meta position to engage in through-space interactions. For small-to-medium-sized substituents, these intramolecular interactions are only present in the (Z)-state and no stabilizing effects in the (E)-state or the transition state via an inversion mechanism occur.[7] This allows the correlation of the kinetically controlled (Z)→(E)-isomerization to thermodynamic quantities. Additionally, by placing substituents in the meta position the influence of electronical effects on the mechanism of isomerization is minimized (‘meta’ rule).[20] Schweighauser as well as Strauss et al. investigated the photochemical properties of different alkyl-substituted AB derivatives and established that even flexible alkyl chains such as n-butyl can cause increased half-lives of the (Z)-isomers, which are up to five times prolonged in comparison to their meta-Me-substituted AB-derivatives (n-decane as solvent, Scheme [1]).[6] [7]

Zoom Image
Scheme 1 Overview of previously reported systems to study alkyl–alkyl interactions using the AB scaffold (top) and the AB designed to investigate aryl–alkyl interactions in this work.
Zoom Image
Figure 1 Overview of AB derivatives 1–9 prepared to investigated alkyl–aryl interactions.

In the work of Schweighauser and Strauss, mostly alkyl–alkyl interactions have been established as the reason for the increased half-life. However, alkyl–aryl interactions are also contributors.[6] [7] [14] [21] To disbar the alkyl–alkyl interactions and put a focus on the aryl–alkyl interactions, nine different AB derivatives were designed, which are substituted in meta position with Me, t-Bu, and n-heptyl on one phenyl ring and with electron-donating (p-OMe), electron-withdrawing (p-NO2), and unsubstituted (p-H) phenyl rings in meta position on the opposite phenyl ring relative to the corresponding azo unit (Figure [1]). For synthesizing the all-meta-substituted ABs of interest with two aryl substituents on one side and two meta-alkyl substituents on the other side (1–9), three different synthetic routes were implemented (Figure [1], Scheme [2]): route 1 was applied for Me-, t-Bu-, and n-heptyl-substituted ABs with unsubstituted phenyl rings (1–3), route 2 for Me-, t-Bu-, and n-heptyl-substituted ABs with OMe-substituted phenyl groups in meta position (4–6), and route 3 for ABs with bis-para-NO2-substituted phenyl rings in meta position (7–9, Scheme [2]). For route 1, anilines 15 and 16 were commercially available; only bis-n-heptyl-aniline (14 ) had to be synthesized starting from 5-nitroisophthalic acid (10). After reduction to 5-nitro-1,3-benzenedimethanol (11) and subsequent oxidation to 5-nitro-1,3-benzenedicarboxaldehyde (12), a Wittig reaction to nitrobenzene 13 was performed.[6] To yield bis-n-heptyl-aniline (14), nitrobenzene 13 was hydrogenated with palladium on activated charcoal under hydrogen atmosphere.[6] Afterwards, anilines 14–16 were condensed in a Baeyer–Mills coupling reaction with nitrosobenzene 20 to the corresponding ABs 1–3. Nitroso compound 20 was synthesized by Suzuki coupling reaction of dibromoaniline (17) with boronic ester 18, followed by oxidation with Oxone® in a biphasic system of DCM/H2O (Scheme [2], top).

Zoom Image
Scheme 2 Synthesis routes 1, 2, and 3 for the preparation of alkyl–aryl-substituted AB 1–9

Route 2 is also based on a Baeyer–Mills coupling reaction as key step to yield ABs 4–6 as final products. The first building block, bis-meta-substituted nitrosobenzenes 24–26, were synthesized by oxidation of the corresponding anilines 14–16 with Oxone®. As second building block, OMe-phenyl-aniline 23 was synthesized by Suzuki coupling reaction of dibromoaniline 17 with boronic ester 22, which was obtained by Miyaura coupling reaction of 4-iodoanisole (21) with bis(pinacolato)diboron (Scheme [2], middle). Route 3 generated the desired ABs 7–9 by Suzuki coupling reaction of ABs 29–31 together with nitro-boronic ester 28, which was synthesized by Miyaura reaction of iodonitrobenzene 27. Before, ABs 29–31 were prepared by Baeyer–Mills coupling reaction of dibromoaniline (17) with the correspon­ding nitrosobenzenes 24–26 (Scheme [2], bottom).

After successful synthesis of AB derivatives 1–9 (Scheme [2]) their rates of the thermal (Z)→(E) isomerization were determined by temperature-controlled UV/Vis spectroscopy at 40 °C in n-octane (Figure [2], Table S3, Table S4). As expected from previous research,[7] meta-di-Me-substituted ABs 1, 4, and 7 exhibit the shortest half-life (11.9 h, 11.8 h, 10.3 h for R3,4 = H, OMe or NO2, respectively). The meta-di-n-heptyl-substituted ABs 3, 6, and 9 exhibit half-lives almost three times longer than the meta-di-Me ABs (31.0 h, 33.0 h, 25.9 h). Among all tested AB derivatives, meta-tert-butyl-substituted ABs 2, 5, and 8 were found to exhibit the longest half-lives (76.5 h, 71.4 h, 64.9 h). ABs with unsubstituted rings 1–3 show similar isomerization kinetics in comparison to ABs with OMe-substituted phenyl rings (4–6). The NO2-substituted ABs 7–9 exhibit a slightly faster isomerization behavior (ca. 15%, independent of the alkyl group attached) compared to their unsubstituted analogues. This effect might be based on the difference in their electronic structure, as ABs with push–pull configurations are generally showing faster isomerization kinetics.[22] However, a uniform mechanism has been previously established for similar meta-substituted ABs confirmed by Exner plot analysis.[7] [23]

Zoom Image
Figure 2 Half-lives and kinetic constants of ABs 1–9

In addition, 1H NOESY NMR spectra were performed exemplary for OMe-substituted ABs 4–6 (Figure [2], full spectra can be found in the Supporting Information). As this technique allows to identify protons which are in close proximity (up to 5 Å) even when they are not covalently bound, it is predestinated to study London dispersion interactions which operate in exactly this range. Therefore, ABs 4, 5, and 6 were irradiated with light of 365 nm to enrich the (Z)-isomer before the 1H NOESY-NMR spectra were recorded (Figure [3]).

Zoom Image
Figure 3 1H NOESY NMR spectra of an enriched concentration of (Z)-isomer of ABs 4, 5, and 6 in CDCl3. The cross-peaks in the enlarged area indicate close proximity of t-Bu and n-heptyl among the protons of the same phenyl ring with the phenyl rings on the opposite side for the (Z)-isomer (middle and right spectra) and only close proximity of Me with the phenyl ring on the same side (left).

As expected for compound 4 no interactions of the methyl groups with the opposite phenyl rings were observed neither in their (Z)- nor in the (E)-state. For the t-Bu-substituted AB 5, though, distinct cross-peaks to the protons of phenyl ring in ortho position, as well as cross-peaks to the protons of the substituted phenyl rings in ortho position can be observed when switched to its (Z)-state, demonstrating the attractive interactions resulting in the longer half-life. Similarly, the 1H NOESY spectrum of the n-heptyl-substituted AB 6 in its (Z)-isomer shows also cross-peaks to the opposite phenyl ring as well as to the protons of the substituted phenyl rings in ortho as well as in meta position. As expected, AB 6 has a shorter half-life than its t-Bu-substituted AB analogue 7. One reason for this observation can be found in the unfavorable contributions of entropy that grow with increasing the flexible alkyl chain. In a previously study, n-Bu chains showed the strongest stabilizing effects, whereas the addition of more methylene groups resulted in lower half-lives.[21] Furthermore, n-heptyl substituents show a higher anisotropic behavior than t-Bu groups, resulting in a in average closer distance, explaining the larger stabilization in the t-Bu derivatives.[24]

Interestingly, the influence of electron-donating or electron-withdrawing substituents on the aryl side is comparatively small on the alkyl–aryl interaction. Besides the small consistent shorter half-life for the NO2 analogues as discussed above, the OMe and H derivatives behave rather uniform. We therefore conclude that the electronic structure of the aromatic London dispersion acceptor in the AB scaffold does not significantly affect the strength of the attractive interactions.

This is in analogy to other studies: Computational studies of CH–π interactions of substituted benzenes with (halo)methanes revealed that the benzene–methane complex showed dispersive forces similar to those of the 1,3,5-trifluorobenzene–methane complex, whereas the dimer of benzene and fluoroform is more stable.[25] Methane–benzene, methane–phenol, and methane–indole also form energetically very similar T-shaped CH–π dimers.[26] Shimidzu and co-workers established via an N-arylimide molecular balance that aryl ethers with different sized and branched carbon chains show only small influence of stabilizing dispersion effects with increasing chain size. However, the observed stabilization is masked by entropy effects, as well as by lone-pair–π interactions of the oxygen.[18] Theoretically, as well as experimentally, the interaction of ethyl or methoxy substituents showed similar dispersive interactions with heterocyclic and nonheterocyclic aromatic compounds, confirming further that the electronic nature of the aryl system does not influence CH–π interactions in a significant way.[27] Furthermore, –CH3 and –CD3 do not show a measurable difference in their interaction with aromatic rings in the experiment or in silico.[28] Our described AB system follows this trend, supporting that the size and shape of the alkyl London dispersion donor is much more important than the electronic properties of the aryl fragment.

In conclusion ABs 1–9 were successfully synthesized via three different synthetic strategies to obtain di-meta-Me-, t-Bu- and n-heptyl-substituted ABs with H-, OMe-, and NO2-substituted phenyl rings on the other benzene moiety.[29] Kinetic data revealed elongated half-lives of the t-Bu-substituted ABs up to six times compared to Me- and n-heptyl-substituted derivatives as expected from previous studies. In accordance with 1H NOESY NMR experiments, the increased half-lives of n-heptyl- and t-Bu-substituted ABs can be attributed to alkyl–aryl interactions, which were not observed for Me-substituted AB derivatives. Altering the electronic structure of the π-donor has no significant effect on the London dispersion interactions, though. Therefore, no drastic change in the isomerization kinetics of OMe- or NO2-substituted aromatic systems was observed in comparison to unsubstituted analogues.


#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Heike Hausmann for NMR support.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1951-2833.
  • Supporting Information

Corresponding Author

Hermann A. Wegner
Institute of Organic Chemistry, Justus Liebig University
Heinrich-Buff-Ring 17, 35392 Giessen
Germany   

Publication History

Received: 12 August 2022

Accepted after revision: 27 September 2022

Accepted Manuscript online:
27 September 2022

Article published online:
28 October 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Overview of previously reported systems to study alkyl–alkyl interactions using the AB scaffold (top) and the AB designed to investigate aryl–alkyl interactions in this work.
Zoom Image
Figure 1 Overview of AB derivatives 1–9 prepared to investigated alkyl–aryl interactions.
Zoom Image
Scheme 2 Synthesis routes 1, 2, and 3 for the preparation of alkyl–aryl-substituted AB 1–9
Zoom Image
Figure 2 Half-lives and kinetic constants of ABs 1–9
Zoom Image
Figure 3 1H NOESY NMR spectra of an enriched concentration of (Z)-isomer of ABs 4, 5, and 6 in CDCl3. The cross-peaks in the enlarged area indicate close proximity of t-Bu and n-heptyl among the protons of the same phenyl ring with the phenyl rings on the opposite side for the (Z)-isomer (middle and right spectra) and only close proximity of Me with the phenyl ring on the same side (left).