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Discovery and Structural Insights into Azulene

Sahid S.K.1, Nasseb Singh1, Manda Sathish2, Alamgir Ahmad Dar3 and Neha Rani Kumar4*

1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal, India

2Centro de Investigación de Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca, Chile

3Research Centre for Residue and Quality Analysis (RCRQA), Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Campus, Srinagar, India

4Department of Chemistry, Dhemaji College, Dhemaji, Assam, India

Abstract

The history of azulene dates back to the 15th century, when it was first identified as the azure-blue intriguing chromophore produced by steam-distilling German chamomile. It was named by Septimus Piesse in 1864. The structure of azulene was first reported by Ruzicka, and its synthesis was reported by Pfau and Plattner in 1939, utilizing indane and ethyl diazoacetate. Azulene is a non-benzenoid aromatic hydrocarbon and is a structural isomer of naphthalene with 10p electrons. It has a planar ring system with a fused pentagon and heptagon, and its groundstate electronic structure is dominated by two Kekulé structures, where as its zwitterionic form has minor contribution to the ground state. Some experimental data indicates that azulene is a non-rigid structure and possesses antisymmetric Kekulé type coordinates, resulting in localized planar Kekulé formations. Due to its unique structural features and properties, azulene is often referred to as aromatic chameleon by organic chemists. Besides that, it also has been a topic of wide interest not only to organic chemists but material scientists and biologists, as well. This chapter highlights the discovery of azulene followed by insights into its structure and its varied applications.

Keywords: Azulene, Kasha's rule, guaiazulene, vetivazulene, organic electronics

1.1 Introduction

Azulene is a naturally occurring, blue-colored, non-benzenoid organic moiety found in various plants and mushrooms. Examples of some of these species that contain azulene include Matricaria chamomilla, Artemisia absinthium, Achillea millefolium, and Lactarius indigo. Azulene and its derivatives have been widely studied because of their potential applications in diverse fields such as medicine, cosmetics, optoelectronic devices, and essential oils. The name azulene found its origin from the Spanish word "azul," which means blue. In the 15th century, azulene was identified as an azure-blue chromophore extracted from German chamomile using steam distillation. In 1864, Septimus Piesse named azulene after discovering it in yarrow and wormwood. The research conducted by Ruzicka laid the foundation for determining azulene structures [1]. In 1937, azulene was first synthesized by Pfau and Plattner [2]. Around 30 years later, Nozoe developed a new method for synthesizing multifunctional azulene derivatives and then azulene gained momentum [3].

Azulene is now a widely studied system in organic, inorganic, pharmaceutical, and theoretical chemistry domains, owing to its unique structure and peculiar properties [4]. Due to its numerous applications, the azulene industry was estimated to be worth USD 360 million in 2023, and the global market for azulene-based industrial products is projected to reach USD 1 billion by 2036. Azulene is an isomer of naphthalene with a similar odor, but it is a blue-colored non-benzenoid aromatic molecule whereas naphthalene is a colorless benzenoid aromatic compound. Vetivazulene (IUPAC name: 4,8-dimethyl-2-isopropylazulene) and guaiazulene (IUPAC name: 1,4-dimethyl-7-isopropylazulene) are classic examples of two terpenoids containing an azulene core structure in their molecules (Figure 1.1) [5]. These compounds are perhaps the unique constituents of pigments in many marine invertebrates, wood oils, and mushrooms. Unlike naphthalene, which is a neutral molecule (µ = 0D), azulene exhibits a permanent dipole (µ = 1.08D) because azulene exists as a dipolar organic molecule, with an electron-deficient seven-membered ring carrying a unit positive charge, and an electron-rich five-membered ring carrying a unit negative charge. The dipolar character of azulene can be explained by the stability of the cyclopentadienyl anion and tropylium cation, which acquire 6p electrons and obey Hückel's (4n+2) p rule of aromaticity. This is likely the primary driving factor for the loss of one electron from the seven-membered ring, while the five-membered ring acquires one electron, resulting in increased stability of the fused hepta-pentacyclic non-benzoid aromatic ring system, known as azulene. Reactivity experiments on azulene and its derivatives also reveal that the seven-membered ring due to its electron-deficient nature is electrophilic, while the five-membered ring due to its electron-rich nature is nucleophilic.

Figure 1.1 Structure of azulene, guaiazulene and vetivazulene.

Azulene shares similar aromatic features, peripheral bond lengths, and Friedel-Crafts substitution processes as naphthalene. It is noteworthy that the stability benefit derived from aromaticity in azulene is around half that of naphthalene. The ground state is dipolar, resulting in a rich color that is uncommon for small unsaturated aromatic systems [6]. This behavior of the azulene ring system has driven synthetic chemists to explore various substituted azulenes with diverse applications in synthetic organic chemistry, medicinal chemistry, and materials science [7, 8].

1.2 Discovery and Synthesis of Azulene

The discovery and structural insights into azulenes have evolved over the past 500 years. Although there has been even earlier documentation of its presence in essential oils. Azulenes are characterized by their intense blue color, which is retained even in high dilution. The blue color of azulenes was initially thought to arise from the copper contamination coming from the distillation step but this was later proven to be intrinsic to the azulene molecules. The azulenes have a boiling temperature significantly higher than sesquiterpenes. However, they co-distill with them, resulting in a deep blue color of the fraction. In Semmler's experiments, around 20 oils, including yarrow, camomile, and cubeb, had blue coloration upon distillation. By 1936, it was estimated that 20% of the 260 known essential oils contained azulenes or their precursors. Finally, in 1864, the term "azulene" was first introduced by Piesse designating the blue oils, which eventually became the parent compound, azulene with the molecular formula C10H8 [9].

Azulenes were initially named by prefixing the name of the source oil to which they were derived. For example, the azulene derivative obtained from guaiol was named guaiazulene, and the azulene obtained from vetiver oil was named vetivazulene. These names were later consolidated into single forms when identical azulenes were found in different sources. Azulenes have been extracted from a variety of plants, including chamomile oil (Matricaria chamomilla L.), Alpinia japonica, vetiver oil, and cajeput oil (Melaleuca leucadendron L.). Besides that, azulenes have also been commonly found in by-products like lignite oil and acetylene pyrolysis. Azulene itself, C¹0H8, was first obtained through the dry distillation of calcium adipate by Pfau and Plattner. However, its natural occurrence remains limited to sources like coucal oil and tobacco smoke [9].

The physical properties of azulenes include a boiling point significantly higher than that of sesquiterpenes and their intense coloration. Initially, Semmler proposed that the intense blue color of azulene arose from a dimeric sesquiterpene structure, similar to indigo. This hypothesis was believed to be true until structural studies confirmed that azulene was indeed a monomer. Kremers and Augspurger confirmed azulene's bicyclic nature through catalytic hydrogenation, yielding decahydroazulene, although some proposed structures failed to explain azulene's color. Ruzicka had done significant research on the structural elucidation of azulene. Structural investigation of azulenes through oxidation of partially hydrogenated azulenes yielded inconclusive results, as azulenes themselves produced only small fragments upon ozonization. However, these results paved the path for the exact structural determination of azulene. Further research by Pfau and Plattner focused on isolating pure azulene products for spectral analysis. Ruzicka and Rudolph made the most appropriate description of azulene in 1926 when they concluded that this intriguing molecule had a bicyclic ring system, albeit not a six-membered aromatic ring, and the bicyclic system had a structural similarity to sesquiterpenes [1].

The first synthesis of azulene dates back to 1937 that was put forward by Plattner and Pfau but over the time this approach was considered disadvantageous as it involved a tedious dehydrogentation step (Scheme 1.1a) [2]. Ziegler-Hafner's method was a useful approach for azulene synthesis, in cases when substituents were to be introduced on the seven-membered ring (Scheme 1.1b) [10]. Nozoe and co-workers demonstrated the most effective azulene synthesis,...