**4. Discussion**

The first description of the possible involvement of microbiota in the pathology of arthritis was published in 1970s when rats raised in germ-free conditions developed severe joint inflammation with 100% penetrance in an adjuvant-induced arthritis model, while conventionally raised controls showed only mild disease at a very low incidence [56].

A fine equilibrium between 'peace-keeping' and potentially pro-inflammatory intestinal and oral bacteria is necessary to keep gut immunity in check and prevent a state of dysbiosis, which might lead to local and distant deleterious consequences in the host. A crucial driver of changes in the gut and oral environments is the inflammatory response of the host. Intestinal and oral inflammations in people are associated with an imbalance in the microbiota, the dysbiosis, which is characterized by a reduced diversity of microbes, a reduced abundance of obligate anaerobic bacteria, and an expansion of facultative anaerobic bacteria in the phylum Proteobacteria, mostly members of the family Enterobacteriaceae.

In regards to RA and gut microbiota, single microorganisms such as *P. copri* might correlate with the development of RA. Pianta A. et al. reported massive concentrations of antibodies against *P. copri* in the sera of RA patients [31]. Impressive advances in sequencing technologies, compelling animal data, and mounting human evidence have suggested that gut microbiota indeed play a part in the pathogenesis of diseases such as autoimmune arthritis. The few studies addressing potential links between the gut microbiota and human inflammatory joint disease have identified dysbiotic patterns that may contribute to initiate or to perpetuate the disease. Obviously, age can greatly contribute to the increase of systemic inflammation (inflammaging), and the microbiota shaped by aging can negatively modulate the outcome of joint diseases. However, the gut microbiota of RA patients seem to be more dysbiotic than those of healthy patients, thus confirming their role as independent of age. An indirect demonstration of the role of microbiota is that gut microbiome (the same for the oral) is perturbed in rheumatoid arthritis and partly normalized after RA-specific treatment [28].

Dysbiosis occurring, for instance, in jejunoileal-bypass, used as alternative to bariatric banding, seems to be associated with arthritis. In these patients, studies have reported a bacterial overgrowth and a deposition of resultant immune complexes in the synovium [57]. However, a very comprehensive human model fitting with the gut–joint axis and dysbiosis can be represented by Whipple's disease, in which the presence of a single bacterium, *Tropheryma whipplei,* overgrowth in the small intestine is su fficient for the development of joint inflammation in predisposed individuals. Similar results have been appointed by some authors regarding the high quantity of *Streptococci* in milk as a theoretical cause of RA [58,59].

A strong evidence of the gut–bone axis and its role in arthritis outcomes has been reported in germ free mice studies. It has been evidenced that these animals do not show arthritis; however, the mono-colonization of particular intestinal bacterium is su fficient to induce arthritis. Thus, gut microbiota have been further confirmed to be a cause of relevant immunological triggers occurring in arthritis pathogenesis [8,60].

Periodontal disease also correlates with new-onset RA patients, and many bacterial clusters related to this disease have been faced in di fferent studies [22–24]. Gene sequencing studies have investigated the subgingival microbiome of patients with RA and compared the results of subjects with osteoarthritis and healthy controls with or without periodontitis. In both cases, literature revealed that specific bacteria biomarker abundance may influence the severity of the osteoarthritic disease. Unfortunately, no unique microbial oral cluster has been identified so far.

Only one study [28] has reported results on the simultaneous e ffect of oral–gut microbiota in RA patients. By collecting fecal, dental and salivary samples in a cohort of RA and healthy donors, this study demonstrated a rate of dysbiosis in the gut and oral microbiomes of RA patients, suggesting an overlap in the abundance and function of species at di fferent body sites that could be partially resolved after RA treatment.

Despite findings which are suggestive of microbiota–bone axis correlation with inflammatory joint disease, research to date remains inconclusive with regard to the final mechanism. We therefore need to identify the priorities for research in order to substantiate and translate these findings. An important and recent review analyzing nine clinical studies [61] compared changes in diversity and taxa present in the microbiome of RA patients with age, gender and weight-matched controls. Despite microbiome diversity being a generic tool to define whether microbial disturbance in the oral or gut environments has occurred, the study of specific bacterial clusters is of great interest to establish the possible etiopathogenetic role of microbiota in arthritis. In RA, a correlation between a pro-inflammatory genotype-HLA related bacteria and some bacterial clusters has been strongly postulated. However, well-defined human studies using NGS and metabolomic approaches are needed to better understand if and when intestinal community composition in patients with joint inflammation di ffers (in addition to improving therapies) by looking at specific bacterial markers for disease presence and progression. Prospective studies evaluating the microbiome–host relationship are indeed necessary to establish not only the potential etiology but also the e ffects of immunosuppressive or anti-inflammatory therapies on microbiota. Another final aim will be to establish how the microbiota can influence therapies per se in OA or RA patients and, subsequently, how they may impact the host's well-being. Table 1a,b shows the main taxa abundances in oral and gut microbiota in OA and RA. To date, interesting and exhaustive data have shown that a connection between microbiomes and joint diseases exists in RA. Other diseases, OA in particular, have received little attention so far, despite some promising, suggestive findings. The gut microbiome, indeed, could be the culprit behind arthritis and joint pain for obese people. A recent paper by Schott E.M. et al. [62] demonstrated that changes in the gut microbiomes of the mice coincided with signs of body-wide inflammation, including in their knees, where the authors induced osteoarthritis with a meniscal tear. Compared to lean mice, osteoarthritis progressed much more quickly in the obese mice, with nearly all of their cartilage disappearing within 12 weeks of the tear.

Though studies have specifically investigated the influence of gut microbiota in OA, pre-clinical data and some observational investigations in humans have suggested a potential relationship between the gut and risk factors of OA. The role of some confounding factors (genes, sex, age, diet, living conditions) needs to be better explored to fully understand the role of gut bacterial biomarkers in OA.

Thus, a deeper understanding of the biological complexities of our 'two genomes' (host and microbial) will help elucidate the factors that trigger inflammation and finally bridge the gap in our knowledge regarding the role of gene–environment interactions in other autoimmune and inflammatory processes involved in disease pathogenesis. Next generation sequencing, metatranscriptomic analysis, and metabolomic approaches may provide yet-greater insight and help to further understand these mechanisms.

There is a justified association between oral and gut microbiomes in arthritis, although the current evidence that the microbiome causes arthritis is far from conclusive. Strategic future studies aiming to improve the understanding of the combined role of gut–oral axis in arthritis as well as the use of "microbiome influencers," such as the probiotics, are mandatory.

#### **5. Highlights of Future Perspectives**

Boxes 1–5 report Microbiome definition and its involvement in RA and OA as well as the need for further studies.

#### **Box 1.** Microbiome definition.

The microbiome is defined as the totality of microorganisms and their genes inhabiting a unique environment; the human microbiome outnumbers human genes by several orders of magnitude.

#### **Box 2.** Tools for studying microbiome.

Understanding of the role of microorganisms in modulating health and disease by NGS and metabolomic technologies will be the new era.

#### **Box 3.** Microbiome and RA link.

Despite the fact that precise causation of RA has not yet been established, several clinical investigations have demonstrated the role of some microorganisms in RA pathogenesis, independently of age.

#### **Box 4.** Microbiome and OA link.

OA is the most common disorder of the musculoskeletal system. The literature has considered the microbiome and the use of some selected probiotics as a possible future therapeutic approach.

#### **Box 5.** Need for further studies.

More studies are needed to assess the role of the microbiome in human arthritis and related diseases in the order to finally elucidate their mechanisms and therapeutic targets.

**Author Contributions:** L.D. conceived and write the paper; G.V.Z., C.L.R., R.M., J.H.V. revised the paper; K.G. and J.P. revised the English and improved the manuscript.

**Funding:** This research received no external funding

**Conflicts of Interest:** The authors declare no conflict of interest


Preface

This book aims to add knowledge to the field of health sciences and public health in particular. The focus is mainly on health psychology; namely the bio-psychosocial approach as a way to embrace health promotion, illness prevention, and health maintenance. The bio-psychosocial approach has contributed immensely to the field of health psychology. As a discipline, health psychology aims to examine how biological, psychological, and social factors influence people's behavior regarding their health status. The psychology of health is a specialty within the discipline of psychology concerned with individual behaviors and lifestyles affecting physical health. In the book by Sarafino (2008:11), the following goals of health psychology were presented:

The recognition of health psychology as a designated field is widely acknowledged. The relationship between mind and body and the effect of one upon the other has been widely debated amongst philosophers, psychologists, and physiologists. Central to the debate has been the question: **Why many people do not do what they know is in their best interest and why some people are more open to the adoption of healthy habits than others?** This is the key question that drives health psychologists to explore and influence lifestyles and behaviors that are conducive or detrimental to good health at the population level. This book is therefore in support of a consistent focus on the role of knowledge in informing people of the risks to themselves that certain behaviors can engender. I acknowledge the good work done by all the authors who contributed to this book. I hope that the readers, especially students, academics, researchers, and other professionals in Health Sciences and related fields, will learn the best practices as provided in the book. The specific chapters included in this book are as follows:

**Simon George Taukeni** University of Namibia, Namibia

**1**

**Chapter 1**

*Simon George Taukeni*

**1. Introduction**

**2. Definitions**

**2.2 Health psychology**

which has become widely accepted:

**2.1 Health**

Introductory Chapter:

Bio-Psychosocial Model of Health

Health psychology explores different ways in the pursuit of getting people to embrace health promotion, illness prevention and health maintenance. As a speciality, health psychology examines how biological, psychological and social factors influence people's behaviour about their health status. The aim of this chapter is to examine possible contributory connections between bio-psychosocial factors and health at the population level. The book explores bio-psychosocial model which can help individuals to develop and maintain healthy lifestyles so as to promote good health and prevent illness. Friedman and Adler [1] noted that the original bio-psychosocial model shaped not only research and theory on health but also the development of health psychology.

Kazarian and Evans [2] suggest that people commonly think about health in terms of an absence of (1) objective signs that the body is not functioning properly and (2) subjective symptoms of disease or injury, such as pain or nausea. World Health Organization defined health as 'a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity' (WHO, 1946 cited in [3]:4). Some health psychologists defined health as a positive state of physical, mental and social well-being not simply the absence of injury or disease that varies over time along a continuum [4]. At the wellness end of the continuum, health is the dominant state. At the other end of the continuum, the dominant state is illness or injury, in which destructive processes produce characteristic signs,

Health psychology is a speciality within the discipline of psychology concerned with individual behaviours and lifestyles affecting physical health. The discipline strives to enhance health, prevent and treat disease, identify risk factors and improve the healthcare system public opinion regarding health issues [5]. Matarazzo in 1980 (as cited in [3]:4) offered a definition of health psychology

*Health psychology is the aggregate of the specific educational, scientific and professional contributions of the discipline of psychology to the promotion and maintenance of health, the prevention and treatment of illness, the identification of*

symptoms or disabilities [4]. For further detail, see **Figure 1**.


**Alkene and Olefin Functionalization by Organoaluminum Compounds, Catalyzed with Zirconocenes: Mechanisms and Prospects Organoaluminum Compounds, Catalyzed with Zirconocenes: Mechanisms and Prospects**

**Alkene and Olefin Functionalization by**

DOI: 10.5772/intechopen.69319

Lyudmila V. Parfenova, Pavel V. Kovyazin, Tatyana V. Tyumkina, Leonard M. Khalilov and Usein M. Dzhemilev Tatyana V. Tyumkina, Leonard M. Khalilov and Usein M. Dzhemilev Additional information is available at the end of the chapter

Lyudmila V. Parfenova, Pavel V. Kovyazin,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69319

### **Abstract**

Alkene and olefin functionalization via addition of electro‐ or nucleophilic reagents is one of the convenient synthetic methods for the insertion of heteroatoms into organic molecules. The use of organometallic reagents in these reactions in combination with the specific catalysts provides high substrate conversion and process selectivity. The intro‐ duction of this approach into the chemistry of organoaluminum compounds leads to the development of chemo‐, regio‐ and stereoselective catalytic methods of alkene and ole‐ fin functionalization. The chapter focuses on the modern concepts of the alkene hydro‐, carbo‐ and cycloalumination mechanisms, that is, the experimental and theoretical data on the intermediate structures involved in the product formation, the effects of the cata‐ lyst and organoaluminum compound structure, reaction conditions on the activity and selectivity of the bimetallic systems. The prospects of the development of enantioselec‐ tive methods using these catalytic systems for the alkene and olefin transformations are considered.

**Keywords:** hydrometalation, carbometalation, cyclometalation, zirconocenes, organoaluminum compounds, reaction mechanism, asymmetric catalysis


**Abstract**

Consumption of fresh leafy greens has been repeatedly reported and linked to pathogenic *Escherichia coli*-associated foodborne illnesses outbreaks. Leafy greens are mostly eaten raw, based on the increased consumers' preferences for natural, nutritious diets. Recent studies indicate the incidence of infections caused by pathogenic *Escherichia coli* remained almost unchanged or even increased. In this context, fresh produces increased the awareness about their primary contamination level, namely the pre-harvest phase. Fully eliminating pathogenic *Escherichia coli* from pre-harvest environment proved to be impossible. Emphasis must be placed on the pre-harvest factors that affect the food safety and, subsequently, on the identification of possible mitigation strategies that can be used on-farm for reducing the risk of leafy greens contamination with pathogenic *Escherichia coli*.

**Keywords:** pathogenic *Escherichia coli*, leafy greens, foodborne illnesses outbreaks, pre-harvest on-farm contamination factors, pre-harvest microbial safety mitigation strategies


*Review* **PD-(L)1 Inhibitors in Combination with Chemotherapy as First-Line Treatment for Non-Small-Cell Lung Cancer: A Pairwise Meta-Analysis**

**Jorge García-González 1,\*,**†**, Juan Ruiz-Bañobre 1,\*,**†**, Francisco J. Afonso-Afonso 2, Margarita Amenedo-Gancedo 3, María del Carmen Areses-Manrique 4, Begoña Campos-Balea 5, Joaquín Casal-Rubio 6, Natalia Fernández-Núñez 5, José Luis Fírvida Pérez 4, Martín Lázaro-Quintela 6, Diego Pérez Parente 7, Leonardo Crama 7, Pedro Ruiz-Gracia 7, Lucía Santomé-Couto 8 and Luis León-Mateos 1,\***

Received: 10 June 2020; Accepted: 28 June 2020; Published: 3 July 2020

**Abstract:** The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. For this purpose, we performed a literature search of randomized controlled trials comparing PD-(L)1 inhibitors plus platinum-based chemotherapy versus chemotherapy alone in stage IV NSCLC patients. Seven clinical trials with 4562 patients were included. In the intention-to-treat wildtype population, PD-(L)1 inhibitor plus chemotherapy was significantly associated with improved progression-free survival (PFS) (Hazard ratio (HR) = 0.61, 95% confidence interval (CI): 0.57–0.65, *p* < 0.001) and overall survival (OS) (HR = 0.76, 95% CI: 0.67–0.86; *p* < 0.001) compared to chemotherapy. A significantly higher overall response rate (ORR) was also observed with the combined strategy (Odds ratio (OR) = 2.12, 95% CI: 1.70–2.63, *p* < 0.001). Furthermore, in all the analyzed subgroups, addition of PD-(L)1 inhibitors to chemotherapy significantly improved efficacy endpoints. Specifically, stratification according to PD-L1 expression revealed a benefit across all patients, regardless of their PFS status. In conclusion, PD-(L)1 blockade added to standard platinum-based chemotherapy significantly improved PFS, OS, and ORR in the up-front treatment of advanced NSCLC.

**Keywords:** non-small-cell lung cancer; immunotherapy; PD-1 inhibitors; PD-L1 inhibitors; chemotherapy; meta-analysis

#### **1. Introduction**

Lung cancer remains the leading cause of cancer-related death worldwide among men and the second among women [1]. Non-small-cell lung cancer (NSCLC), which is the most common type, accounts for 80% to 85% of all lung cancer diagnoses [2]. It is frequently diagnosed in the advanced stage, with 5-year survival rates ranging from 0% to 5% with chemotherapy, the only systemic therapeutic strategy available for decades [3]. In this regard, blockade of the programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis in particular has opened up a new horizon in the lung cancer therapeutic landscape, increasing overall survival (OS) not only in patients with advanced NSCLC but also in patients with stage III NSCLC and extensive-stage small-cell lung cancer [4–6].

Since 2015, three different PD-(L)1 inhibitors have been approved by the European Medicines Agency (EMA) and/or the U.S. Food and Drug Administration (FDA) for the treatment of metastatic NSCLC (mNSCLC) [7]: two anti-PD-1 antibodies (nivolumab and pembrolizumab) and one anti-PD-L1 antibody (atezolizumab), indicated for patients regardless of their PD-L1 expression status (nivolumab and atezolizumab) or for PD-L1-positive patients only (pembrolizumab). All of them have demonstrated an improvement in OS compared to docetaxel in second-line therapy [8–10]. In the first-line setting, results from the KEYNOTE 024 trial demonstrated that, compared with platinum-based chemotherapy, OS, progression-free survival (PFS), and overall response rate (ORR) were significantly improved in patients with PD-L1 expression on at least 50% of tumor cells and without oncogenic driver mutations [11,12]. Interestingly, an additional study assessing pembrolizumab efficacy versus chemotherapy using a PD-L1 tumor proportion score (TPS) of 1% or greater (KEYNOTE-042 [13]) demonstrated improved OS for the full cohort, which, despite being higher for higher PD-L1 expression, supported a potential extended role of pembrolizumab monotherapy as a standard first-line treatment for PD-L1-expressing advanced/metastatic NSCLC [14]. In contrast, nivolumab did not demonstrate statistically significant survival benefits in previously untreated PD-L1-positive mNSCLC (CheckMate-026 [15]).

Nevertheless, many patients with advanced NSCLC do not benefit from PD-(L)1 inhibitors, either in the first line or in the second or successive lines of treatment. The search for reliable predictive biomarkers of response to these drugs is therefore essential to improve patient outcomes.

The potential synergistic effects of combining chemotherapy and immunotherapy to improve the antitumor activity of anti-PD-(L)1 monotherapy were initially suggested in preclinical studies [16] (Apetoh, 2015 #16) and were further demonstrated in several clinical trials [4–6,17–25]. However, although promising outcomes have been reported, several questions remain unanswered, such as the potential real benefit for all patients at the expense of increased toxicity or the possible molecular factors that could predict the benefit of this combined therapeutic strategy.

The objective of this study was to evaluate the efficacy of the combined strategy by conducting a pairwise meta-analysis (MA) of the available information on PD-(L)1 inhibitors in combination with chemotherapy in the first-line treatment of patients with advanced NSCLC.


*4.1. Eve's Attack*

The intensity of Eves' attack is affected by the spatial distribution. In Figure 3a, when we compare the blue line with the red and yellow line, respectively, we find that the covering radius *RS* has little effect on STP while density *λp* significantly reduces the STP. However, in Figure 3b, both the value of *RS* and *λp* have significant impacts on the STP. The reason is that the SNR of multiple eavesdroppers in the non-colluding case depends on the 'nearest' Eve which has the best channel quality while the SNR in the colluding case only depends on the total number. The parameter *RS* can barely increase the chance of the 'nearest' Eve as the THz transmit power quickly attenuates with the distance but indeed increases the total number of them. Therefore, from Eves' perspective, they have to focus on 'a better channel' or 'a better location' rather than the total number in a non-colluding

case, as we can see the STP of the case when *NE* = 17 performs even better than the STP when *NE* = 7 in Figure 3a.

**Figure 3.** Secure transmission probability (STP) under different *RS* and *λp* for (**a**) non-colluding case and (**b**) colluding case. Parameters are given by: *G* = 25 dBi; *N* = 5; *f* = 300 GHz; and *P* = −10 dBm.

In Figure 4, we use normalized secrecy capacity [30] to show the extent to which Eves reduce the secrecy capacity in non-colluding and colluding cases, respectively. It is shown that for *d*2 = 20, the existence of Eves reduces the original capacity by 20% in non-colluding case and by nearly 40% in colluding case.

**Figure 4.** The normalized secrecy capacity as a function of *d*2 in the non-colluding and colluding cases. Here, all the eavesdroppers have the same distance *d*2 to the PEC and the channel fading is ignored. Other parameters are given by: *G* = 25 dBi; *f* = 300 GHz; *P* = −10 dBm; *RS* = 15 m; and *d*3 = 1 m.

Eve can move the PEC closer to Alice to strengthen the attack. In Figure 5, we find that the ESC monotonically increases with *d*3 (PEC) while decreasing with the *d*1 (Bob). In addition, the parameters *d*1 and *d*3 may have interacted with each other. For example, for *d*1 = 3, a unit increase in *d*3 will give birth to the improved ESC by ΔESC = 1.45. For *d*1 = 5, ΔESC becomes 1.95. That is to say, *d*3(*d*1) may exhibit a different effect when the other factor changes. Furthermore, if PEC is located in the midpoint between Alice and Bob, the ESC will not change significantly with the increase in *d*1, as we can see that the white line in Figure 5 nearly remains unchanged at ESC = 4.85.

**Figure 5.** Ergodic secrecy capacity (ESC) as a function of *d*1 (Alice–Bob) and *d*3 (Alice–PEC) for (**a**) non-colluding eavesdroppers and (**b**) colluding eavesdroppers. Other parameters are given by: *G* = 25 dBi; *N* = 3; *f* = 300 GHz; *P* = −10 dBm; *RS* = 15 m; and *λp* = 0.015.

Eve can increase the size of PEC to strengthen the attack. In Figure 6a, we find that the STP will decrease when the radius *a* rises from 20 mm to 40 mm, regardless of whether it is in the non-colluding case or in the colluding case. As shown in Figure 2, as *a* grows from 20 mm to 40 mm, the electromagnetic field around the PEC will be augmented and hence Eves obtains better signal quality. Additionally, we find that Eves benefit from increasing *a* to various degrees when the location of PEC *d*3 changes. For *d*3 = 5 m, as shown in Figure 6b, reducing *a* from 10 mm to 50 mm will lead to an ESC decrease of 36%. For *d*3 =1m, however, reducing *a* from 10 to 50 decreases the ESC by 87% to nearly 0 which means that Eves can almost intercept all the information. Since being too near to Alice will increases the risk of being detected, Eve's strategy is to select a proper size and optimal location in such a way she can obtain as good a signal strength as possible and hide herself simultaneously.

**Figure 6.** (**a**) Influence of radius *a* on STP. (**b**) ESC versus radius *a* under different PEC location *d*3. The solid line describes the non-colluding case while the dashed line describes the colluding case. Other parameters are given by: *G* = 25 dBi; *N* = 3; *f* = 300 GHz; *P* = −10 dBm; *RS* = 15 m; and *λp* = 0.04.


*Article* **Donor-Type Nickel–Dithiolene Complexes Fused with Bulky Cycloalkane Substituents and Their Application in Molecular Conductors**

**Kazuya Kubo 1,\*, Mamoru Sadahiro 1, Sonomi Arata 1, Norihisa Hoshino 2, Tomofumi Kadoya 1, Tomoyuki Akutagawa 2, Reizo Kato 3 and Jun-ichi Yamada 1**

**Abstract:** The effects of substituents on the arrangement of metal–dithiolene complexes based on π-conjugated systems, which are extensively used to synthesize various functional materials, have not been studied adequately. New donor-type nickel–dithiolene complexes fused with bulky cycloalkane substituents [Ni(Cn-dddt)2] (C5-dddt = 4a,5,6,6a-pentahydro-1,4-benzodithiin-2,3-dithiolate; C6 dddt = 4a,5,6,7,8,8a-hexahydro-1,4-benzodithiin-2,3-dithiolate; C7-dddt = 4a,5,6,7,8,9,9a-heptahydro-1,4-benzodithiin-2,3-dithiolate; and C8-dddt = 4a,5,6,7,8,9,10,10a-octahydro-1,4-benzodithiin-2,3 dithiolate) were synthesized in this study. All the complexes were crystallized in cis-[Ni(cis-Cndddt)2] conformations with cis-oriented (*R*,*S*) conformations around the cycloalkylene groups in the neutral state. Unique molecular arrangements with a three-dimensional network, a one-dimensional column, and a helical molecular arrangement were formed in the crystals owing to the flexible cycloalkane moieties. New 2:1 cation radical crystals of [Ni(C5-dddt)2]2(X) (X = ClO4 − or PF6 −), obtained by electrochemical crystallization, exhibited semiconducting behaviors (*ρ*rt = 0.8 Ω cm, *E*a = 0.09 eV for the ClO4 − crystal; 4.0 Ω cm, 0.13 eV for the PF6 − crystal) under ambient pressure due to spin-singlet states between the dimers of the donor, which were in accordance with the conducting behaviors under hydrostatic pressure (*ρ*rt = 0.2 Ω cm, *E*a = 0.07 eV for the ClO4 − crystal; 1.0 Ω cm, 0.12 eV for the PF6 − crystal at 2.0 GPa).

**Keywords:** nickel–dithiolene complex; cycloalkane substituent; molecular conductor

#### **1. Introduction**

Organic π-conjugated molecules, including tetrathiafulvalene (TTF) skeletons, are among the most common building blocks for the realization of various functional materials [1]. The TTF molecule has an electron donor ability, which can help realize various charge transfers and produce radical cation crystals. The TTF-TCNQ (TCNQ: 7,7,8,8 tetracyanoquinodimethane) is a prototype of charge-transfer compounds, where the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) bands of the open-shell donors and acceptors, respectively, contribute to the conduction [2,3]. It is the first organic conductor to exhibit a metallic conductivity within a wide temperature range with a minimum of 59 K, where a sharp metal-to-insulator transition is observed [4]. Moreover, TTF has attracted significant research attention with the discovery of superconducting salts [5–8] based on TTF derivatives such as atetramethyltetraselenafulvalene (TMTSF) [9], bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) [10,11], and dimethyl(ethylenedithio)diselenadithiafulvalene (DMET) [12,13]. The conducting properties of molecular-based materials are significantly influenced by their molecular arrangements in

**Citation:** Kubo, K.; Sadahiro, M.; Arata, S.; Hoshino, N.; Kadoya, T.; Akutagawa, T.; Kato, R.; Yamada, J.-i. Donor-Type Nickel–Dithiolene Complexes Fused with Bulky Cycloalkane Substituents and Their Application in Molecular Conductors. *Crystals* **2021**, *11*, 1154. https:// doi.org/10.3390/cryst11101154

Academic Editor: Alberto Girlando

Received: 26 August 2021 Accepted: 14 September 2021 Published: 23 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

crystal form. The cation radicals of BEDT-TTF and bis(ethylenedithio)tetraselenafulvalene (BETS) can crystallize in various donor packing motifs, including α-, β-, θ-, κ-, and λ-type arrangements by combination with inorganic, organic, and organometallic anions [14–18]. Alternative strategies for tuning the molecular arrangements in organic conductors were reported based on organic synthesis techniques. A potential method involves the direct introduction of various substituents into the TTF or BEDT-TTF skeletons [19–42]. Kimura et al. reported that meso-2-(5,6-dihydro-1,3-dithiolo[4,5-b][1,4]dithiin-2-ylidene)- 5,6-dihydro-5,6-dimethyl-1,3-dithiolo[4,5-b][1,4]dithiin (meso-DMBEDT-TTF) forms a superconducting crystal β-(meso-DMBEDT-TTF)2PF6 with a transition temperature at 4.3 K under a hydrostatic pressure of 4.0 kbar due to a checkerboard-type charge order state on the donor molecules [43,44]. Another alternative method involves the introduction of bulky cycloalkane moieties into the donor molecules to determine the stacking of the donor molecules; thus, the ratio of the on-site Coulomb repulsion energy *U* to the bandwidth *W* can be controlled by changing *W* for the organic Mott insulators based on the enhanced steric hindrance in the radical cation crystals of CnDT-EDO-TTF (*n* = 5, 6, 7, 8; *cis*-1,2-cycloalkylene-1,2-dithio)ethylenedioxytetrathiafulvalene] and its derivatives (Scheme 1) [45,46].

**Scheme 1.** Organic components of molecular conductors.

Metal bis-dithiolene complexes can exhibit various oxidation states [47] and have smaller HOMO–LUMO gaps than those of the organic donors [48,49], which is advantageous for the components of molecular conductors. Electron-acceptor type [M(dmit)2] (M = Pd, Pt; dmit = 1,3-dithiole-2-thion-4,5-dithiolete) complexes with small gaps between the HOMO and LUMO form dimer structures. These structures induce crossing HOMO– LUMO band inversions through metal–metal interactions in the solid state, which provide various conducting, magnetic, and other physical properties by combining with closed-shell cations [47,50–52]. The electron-donor-type metal bis-dithiolene complexes [M(dddt)2] (M = Ni, Pd, Pt, and Au; dddt = 5,6-dihydro-1,4-dithiine-2,3-ditholate) are candidate materials for the development of molecular conductors due to their orbital symmetries, which are similar to those of BEDT-TTF [53–56]. A cation radical crystal, [Ni(dddt)2]3(AuBr2)2, is the first metal based on the donor-type metal–dithiolene complexes exhibiting metallic behavior down to at least 1.3 K [57]. Recently, Kato et al. reported a single-component molecular Dirac electron system based on Pd(dddt)2 that exhibits temperature-independent resistivity under high hydrostatic pressures [58–63]. The conducting and magnetic properties exhibited by the molecular crystals based on the dithiolene complexes are significantly dependent on the molecular arrangements of the metal–dithiolene complexes and organic molecular conductors. In the case of molecular conductors based on metal–dithiolene complexes, the molecular arrangements of the complexes are dependent on the combination of counter cations and anions in the crystals [47,48]. However, there are few reports on the substituent effects on the molecular arrangement, which influences the physical properties, despite the advantages of the components of molecular conductors [64,65]. Thus, we designed novel donor-type metal bis-dithiolene complexes [Ni(Cn-dddt)2] formed by a [Ni(dddt)2] skeleton fused with bulky cycloalkane rings and investigated the substituent effects on the arrangement of the complexes and their physical properties (Scheme 2). Donor organic molecules fused with bulky substituents such as cycloalkane and dioxane moieties can form unique molecular arrangements in the crystals [66], which exhibit superconducting and metallic behaviors [45,46,67–69].

**Scheme 2.** Metal–dithiolene complexes as components of molecular conductors.

In this paper, we report the donor abilities of novel donor complexes [Ni(Cn-dddt)2] with two cycloalkane rings (C5-dddt = 4a,5,6,6a-pentahydrro-1,4-benzodithiin-2,3-dithiolate; C6-dddt = 4a,5,6,7,8,8a-hexahydro-1,4-benzodithiin-2,3-dithiolate; C7-dddt = 4a,5,6,7,8,9,9aheptahydro-1,4-benzodithiin-2,3-dithiolate, and C8-dddt = 4a,5,6,7,8,9,10,10a-octahydro-1,4-benzodithiin-2,3-dithiolate) based on electrochemical measurements and electronic absorption spectra. The packing motifs of the neutral [Ni(Cn-dddt)2] (*n* = 5, 6, 7, 8) were discussed based on X-ray crystallographic analysis results. Furthermore, electronic features of new cation radical crystals [Ni(C5-dddt)2]2[X] (X = ClO4 − and PF6 −) were revealed using electrical resistivity, magnetic measurements, and band calculations based on the crystal structures.

#### **2. Materials and Methods**

#### *2.1. Materials*

All the solvents were of analytical grade and were used without further purification. All the reactions were performed in a nitrogen atmosphere. Oligo(1,3-dithiole-2,4,5 trithione) ((C3S5)x) [70] and (Bu4N)[Ni(dddt)2] [56] were prepared using a previously reported method.

*2.2. Synthesis*

2.2.1. Synthesis of 4,5-Cis(cyclopentalenedithio)-1,3-dithiole-2-thione (**L1**),

4,5-Cis(cyclohexylenedithio)-1,3-dithiole-2-thione (**L2**),

4,5-Cis(cycloheptalenedithio)-1,3-dithiole-2-thione (**L3**), and

4,5-Cis(cyclooctalenedithio)-1,3-dithiole-2-thione (**L4**)

In a nitrogen atmosphere, cyclopentene (25 mmol) was dissolved in 1,2-dichloroethane (25 mL), and oligo(1,3-dithiole-2,4,5-trithione) (10 mmol) was added. The resulting suspension was heated to 135 ◦C for 14 h with stirring, and the reaction mixture was filtered to remove insoluble precipitates. The evaporation of the filtration in vacuo, followed by purification of the residue by column chromatography (SiO2, carbon disulfide (CS2)-hexane 1:3), yielded 67.6% 4,5-cis(cyclopentalenedithio)-1,3-dithiole-2-thione (**L1**) as yellow crystals after recrystallization from hot ethanol (EtOH). Moreover, 4,5-cis(cyclohexylenedithio)- 1,3-dithiole-2-thione (**L2**), 4,5-cis(cycloheptalenedithio)-1,3-dithiole-2-thione (**L3**), and 4,5 cis(cyclooctalenedithio)-1,3-dithiole-2-thione (**L4**) were obtained using a similar procedure with corresponding cycloalkenes as starting materials, yielding 32.7% **L2**, 77.6% **L3**, and 69.2% **L4**.

```
2.2.2. Synthesis of 4,5-Cis(cyclopentalenedithio)-1,3-dithiole-2-one (L1-

                                                                           ) and
4,5-Cis(cyclohexylenedithio)-1,3-dithiole-2-one (L2-

                                                       ),
4,5-Cis(cycloheptalenedithio)-1,3-dithiole-2-one (L3-

                                                        ), and
4,5-Cis(cyclooctalenedithio)-1,3-dithiole-2-one (L4-

                                                      )
```
Mercuric acetate (1.5 mmol) was added to a solution of **L1***-* (1 mmol) in tetrahydrofuranacetic acid (2:1, 45 mL), and the resulting white suspension was stirred for 30 min at 20 ◦C. The resulting white precipitate was removed by filtration using Celite and washed thoroughly using chloroform. The combined organic phases were washed using water (2 × 100 mL), saturated sodium hydrogen carbonate (2 × 100 mL), and water (1 × 100 mL), and then they were dried using magnesium sulfate. The removal of the solvent in vacuo yielded 98% 4,5-cis(cyclopentalenedithio)-1,3-dithiole-2-one (**L1***-* ) as large pale yellow needle crystals. Moreover, 4,5-cis(cyclohexylenedithio)-1,3-dithiole-2-one (**L2***-* ), 4,5-cis(cycloheptalenedithio)-1,3-dithiole-2-one (**L3***-* ), and 4,5-cis(cyclooctalenedithio)-1,3 dithiole-2-one (**L4***-* ) were obtained using a similar procedure; thus yielding 97% **L2***-* , 98% **L3***-* , and 97% **L4***-* .

2.2.3. Synthesis of Monoanionic Complexes (Bu4N)[Ni(Cn-dddt)2] (*n* = 5, **1**; *n* = 6, **2**; *n* = 7, **3**; and *n* = 8, **4**)

Sodium (3.0 mmol) and **Lm'** (m = 1–4) (1.2 mmol) were dissolved in EtOH (15 mL). The resulting clear orange solution was dropped into an EtOH solution (15 mL) of NiCl2·6H2O (0.6 mmol) for 30 min with stirring. The resulting solution had a dark purple color. It was stirred in the air for a further 30 min, and the color changed to dark green as the reaction proceeded. After filtration to remove insoluble precipitates, one equivalent tetrabutylammonium bromide was added to the solution, and a dark green solid precipitated immediately. The green solids of monoanionic complexes **1**–**4** were collected by filtration and recrystallized using acetone. The yields for **1**, **2**, **3**, and **4** were 79.6%**,** 63.0%, 46.4%, and 38.8%, respectively.

2.2.4. Synthesis of Neutral Complexes [Ni(Cn-dddt)2] (*n* = 5, **5**; *n* = 6, **6**; *n* = 7, **7**; and *n* = 8, **8**)

An acetonitrile (CH3CN) (50 mL) solution of iodine (1.3 mmol) was added to a CH3CN solution (100 mL) of monoanionic complexes **1**–**4** (0.23 mmol). Black precipitates of **5–8** were obtained immediately. The precipitates of the neutral complexes were collected by filtration, washed using CH3CN and methanol, and dried under reduced pressure. Black block-shaped single crystals of the neutral complexes **5–8**, which were suitable for X-ray crystallographic analyses, were obtained by recrystallization from their carbon disulfide solutions. The yields for **5**, **6**, **7**, and **8** were 69.2%, 31.5%, 62.9%, and 36.8%, respectively. The elemental analysis results for these complexes are summarized in Table 1.

2.2.5. Synthesis of Radical Cation Crystals [Ni(C5-dddt)2]2[ClO4] (**9**) and [Ni(C5-dddt)2]2[PF6] (**10**)

Dichloromethane (CH2Cl2) solutions (10 mL) of **5** (0.03 mmol) containing (Bu4N)(X) (X = ClO4 or PF6) (0.09 mmol) as electrolytes were electrolyzed under constant-current conditions (3 μA) for three days in an H-shaped cell equipped with platinum wire electrodes in an argon atmosphere at 20 ◦C. Black crystals of **9** and **10** were formed on the anode surface. The chemical formulas of **9** and **10** were confirmed by X-ray crystal structural analyses.

#### *2.3. Physical Measurements*

#### 2.3.1. Elemental Analyses

The analyses of the carbon, hydrogen, and nitrogen elements were performed using a PERKIN-ELMER 240 C elemental analyzer for **1**, **3**, **7**; and a Yanako MT-6 CHN CORDER for **2**, **4**, **5**, **6**, and **8**. The elemental analyses of the nickel and sulfur atoms of the neutral complexes **5–8** were performed using a SHIMADZU ICPS-1000IV by the Chemical Analysis Team of AD&SD in RIKEN.

#### 2.3.2. Electrochemical Measurements

Cyclic voltammograms of monoanionic complexes **1**–**4** were obtained using acetonitrile solutions (1 × 10−3 mol L−1) with (Bu4N)(ClO4) (0.1 M) as a supporting electrolyte and recorded using a BAS ALS/[H] CH Instruments Model 610 electrochemical analyzer combined with an Ag/Ag+ reference electrode, platinum counter electrode, and glassy carbon working electrode at room temperature. The scan rate of the measurements was 100 mV/s.

#### 2.3.3. Electronic Absorption Spectra

The electronic absorption spectra (300–1600 nm) of **1**–**8** in CH2Cl2, CH3CN, and benzene solutions (5 × 10−5 mol L−1) at room temperature were measured by the Chemical Analysis Team of AD&SD in RIKEN using a Shimadzu UV-3100 system.

#### 2.3.4. Electrical Resistivity

The temperature dependence of the electrical resistivity was measured using the standard four-probe method at ambient pressure for **9** and **10**. Gold wires (15 μm in diameter) were attached to the crystal with a carbon paste. Resistivity measurements under the hydrostatic pressure of the salt were performed within the range from 0.3–1.8 GPa using a clamp-type piston-cylinder high-pressure cell [71,72].

#### 2.3.5. Magnetic Susceptibility

The magnetic susceptibilities of **9** (15 mg) and **10** (20 mg) were measured in a magnetic field of 1 T using a superconducting quantum interference device (SQUID) magnetometer (Quantum Design, MPMS-XL7) within the temperature range of 2–300 K.

#### 2.3.6. Band Calculation

The intermolecular overlap integrals (*S*) between the frontier orbitals were calculated based on the extended Hückel molecular orbital (MO) method. The semi-empirical parameters for the Slater-type atomic orbitals were obtained from the literature [73–75].

#### 2.3.7. Crystal Structure Determinations of **L2**–**L4**, Neutral Complexes **5**–**8**, and Radical Cation Crystals **9** and **10**

Crystallographic data for the single crystals of **L2**–**L4**, **5**–**8**, and **9**–**10** were obtained using a Rigaku MicroMax-007 diffractometer with a multilayer mirror monochromated Mo-K*α* (*λ* = 0.71073 Å) and charge-coupled device detector at 93 K. Structural refinements were carried out using the full-matrix least-squares method on *F*2 [76]. The structures were determined and refined using SHELXL-2018 in the Olex2 software package [77,78]. The parameters were refined using anisotropic temperature factors, with the exception

of the hydrogen atoms, which were parametrically refined using the riding model with a fixed C-H bond distance of 0.95 Å. The crystallographic data for **L2**–**L4**, **5**–**8**, and **9**–**10** are summarized in Tables 2–4, respectively.

**Table 2.** Crystallographic data for neutral complexes **L2**–**L4**.

a *R*(*F*2) = Σ (*F*o 2 − *F*c 2)/Σ *F*o 2; b *wR*(*F*2)=[Σ *w*(*F*o 2 − *F*c 2) 2/Σ *w*(*F*o 2) 2] 1/2 and *w*−1 = [Σ2 (*F*2) + (0.0278*P*) 2 + 0.7843*P*] for **L2**; *w*−1 = [Σ2 (*F*2) + (0.0450*P*) 2 + 0.3773*P*] for **L3**; and *w*−1 = [Σ2 (*F*2) + (0.0379 *P*) 2 + 0.4043*P*] for **L4** (where *P* = (*F*o 2 + 2*F*c 2)/3).

**Table 3.** Crystallographic data for neutral complexes **5**–**8**.

**Table 3.** *Cont.*

a *R*(*F*2) = Σ (*F*o 2 − *F*c 2)/Σ *F*o 2, b *wR*(*F*2)=[Σ *w*(*F*o 2 − *F*c 2) 2/Σ *w*(*F*o 2) 2] 1/2 and *w*−1 = [Σ2 (*F*2) + (0.0341*P*) 2 + 0.4506*P*] for **5**; *w*−1 = [Σ2 (*F*2) + (0.0110*P*) 2 + 9.3099*P*] for **6**; *w*−1 = [Σ2 (*F*2) + (0.0275*P*) 2 + 0.2769*P*] for **7**; and *w*−1 = [Σ2 (*F*2) + (0.0195*P*) 2 + 10.6333*P*] for **8** (where *P* = (*F*o 2 + 2*F*c 2)/3).

**Table 4.** Crystallographic data for the radical cation crystals **9** and **10**.

a *R*(*F*2) = Σ (*F*o 2 − *F*c 2)/Σ *F*o 2; b *wR*(*F*2)=[Σ *w*(*F*o 2 − *F*c 2) 2/Σ *w*(*F*o 2) 2] 1/2 and *w*−1 = [Σ2 (*F*2) + (0.0186*P*) 2 + 4.1733*P*] for **9**; and *w*−1 = [Σ2(*F*2) + (0.0403*P*) 2 + 1.0162*P*] for **10** (where *P* = (*F*o 2 + 2*F*c 2)/3).

#### **3. Results and Discussion**

*3.1. Synthesis of Complexes* **1**–**8**

3.1.1. Syntheses and Molecular Structures of Precursors **L1**–**L4**

One of the most effective methods for synthesizing various TTF derivatives and their precursors involves [2 + 4] cycloadditions of (C3S5)x (as 4π) and a molecule that involves one of its external double bonds (as 2π) [79]. This reaction is stereospecific, similar to the [2 + 4] cycloaddition of tetrathiooxalate with alkanes, thus providing a cis-oriented compound [80]. Precursors **L1–L4** were synthesized using a modified version of a method outlined in a previous study, by the [2 + 4] cycloadditions of (C3S5)x and cycloheptene, cyclohexene, cycloheptene, and cyclooctene [81]. The cycloalkylene residues were cisoriented with respect to the newly formed 1,4-dithiene rings. Single crystals of **L1**–**L4** were obtained by recrystallization from their dichloromethane solutions, which were suitable for X-ray crystallographic analyses, with the exception of **L1**. Figure 1 presents the molecular structures of two crystallographically independent molecules A and B in the crystal of **L2**. The fused cyclohexane moieties in molecules A and B formed cis-oriented (*R*,*S*) conformations at the two carbons C(4)-C(5) and C(13)-C(14), respectively. Stable chair-type configurations of the cyclohexylene groups were observed for molecules A and B. A similar cis-oriented conformation was observed in the crystals of 4,5-(l,4-dioxanediyl-2,3-dithio)-l,3-dithiole-2-thione and 4,5-(cis-cyclohexylenedithio)-1,3-dithiole-2-one [82,83]. The bond distances of C=C and C=S were 1.349 Å and 1.648 Å for molecule A, and 1.352 Å and 1.648 Å for molecule B. The angles between the planes formed by S(1)-C(2)-C(3)-S(2) and S(3)-C(2)-C(3)-S(4) in molecule A and S(6)-C(11)-C(12)-S(7) and S(8)-C(11)-C(12)-S(9) in molecule B were 3.86◦ and 3.08◦, respectively. The bond distances and angles indicate that the C3S5 moieties of molecules A and B formed similar planar structures. The torsion angles around the fused cyclohexyl group in molecule A were −71.20◦, −6.76◦, and 56.18◦ for C(2)- S(1)-C(4)-C(5), C(3)-S(2)-C(5)-C(4), and S(1)-C(4)-C(5)-S(2), respectively. The corresponding torsion angles in molecule B were −62.56◦, −26.37◦, and 63.91◦ for C(11)–S(6)–C(13)-C(14), C(12)-S(7)-C(14)-C(13), and S(6)-C(13)-C(14)-S(7), respectively. The comparison of the torsion angles between molecules A and B revealed that the fused cyclohexylene group in molecule A deviated more from the C3S5 plane at the S(1) and S(2) positions than that of molecule B.

**Figure 1.** Molecular structures of two crystallographically independent molecules, (**a**) **A** and (**b**) **B**, in the crystal of **L2** along the vertical, parallel, and end-on directions on the C3S5 molecular plane with atom labels.

Figure 2 presents the molecular structures of **L3** and **L4**. The fused cycloheptane and cyclooctane moieties formed cis-oriented (*R*,*S*) conformations at the two carbons C(4) and C(5), respectively, in addition to molecule **L2**. Twist-chair- and boat-chair-type configurations of the cycloheptylene and cyclooctylene groups were formed in **L3** and **L4**, which were observed in the crystals of CnDT-EDO-TTF (*n* = 7, 8) [45]. The C3S5 moieties of **L3** and **L4** were planar structures, as observed in the crystal of **L2**; where the bond lengths C(1)=S(5) and C(2)=C(3) and the angles between the planes formed by S(1)-C(2)-C(3)-S(2) and S(3)-C(2)-C(3)-S(4) were 1.656 Å, 1.355 Å, and 2.89◦ for **L3**; and 1.647 Å, 1.344 Å, and 2.75◦ for **L4**, respectively. The torsion angles around the fused cycloalkylene groups of C(2)-S(1)-C(4)-C(5), C(3)-S(2)-C(5)-C(4), and S(1)-C(4)-C(5)-S(2) were 57.68◦, 42.60◦, and −72.47◦ for **L3;** and 58.00◦, 41.11◦, and −72.18◦ for **L4**, respectively.

**Figure 2.** Molecular structures of (**a**) **L3** and (**b**) **L4** along the vertical, parallel, and end-on directions on the C3S5 molecular plane with atom labels.

3.1.2. Molecular and Crystal Structures of Neutral Complexes **5**–**8**

We successfully obtained single crystals of the neutral complexes that were suitable for X-ray crystallographic analysis by recrystallization from CS2 solutions of complexes **5**–**8**. The synthetic procedure for the neutral complexes is shown in Scheme 3. The precursors of **L1**–**L4** formed cis-oriented (*R*,*S*) conformations around the cycloalkylene groups due to the [2 + 4] cycloadditions. Using the synthetic procedures shown in Scheme 3, Monoanionic complexes **1**–**4** were obtained as mixtures, including diastereomeric isomers (Bu4N){trans- [Ni(cis-Cn-dddt)2]} and (Bu4N){cis-[Ni(cis-Cn-dddt)2]}, due to the conformations between the two cycloalkylene groups in the molecules. The oxidation of Monoanionic complexes **1**–**4** resulted in the formation of mixtures of diastereomeric isomers for neutral complexes **5**–**8** (Scheme 4). From the recrystallization processes, single crystals of neutral complexes **5**–**8** were formed by the trans-isomers.

**Scheme 3.** Synthetic procedure of neutral [Ni(Cn-dddt)2] complexes.

**Scheme 4.** Diastereomeric isomers of the trans- and cis-[Ni(cis-C5-dddt)2] complexes.

The selected bond lengths and angles of the neutral complexes in crystals **5**–**8** are summarized in Table 5. In molecules of **5**–**8**, square planar co-ordinations were constructed around the Ni atoms, similar to previously reported square planar Ni-dithiolene complexes such as [Ni(dddt)2] in a neutral state [84–91].

**Table 5.** *Cont.*

a) The S(2 ) atoms were positioned by the following symmetry operations of S(2) atoms: (2-x, 1-y, 1-z) for **5**, (1-x, 1-y, -z) for **7**, and (-x, 1-y, 1-z) for **8**.

Figure 3 presents the molecular structure of **5**. One half of the trans-[Ni(cis-C5-dddt)2] molecule was crystallographically independent with an inversion center on the nickel atom in the crystals of **5**. The torsion angles around the fused cyclopentylene group of the molecule were 45.93◦, 42.06◦, and −62.81◦ for C(1)-S(3)-C(3)-C(4), C(2)-S(4)-C(4)-C(3), and S(3)-C(3)-C(4)-S(4), respectively. The approximate geometry of the [Ni(dddt)2] moiety in crystal **5** was highly similar to those of an anionic [Ni(dddt)2] − molecule [92]. The cyclopentylene ring of **5** adopted a folded conformation from the [Ni(dddt)2] moiety with the trans-orientation, which is different from the conformation observed in (Ph4P){trans- [Ni(cis-C5-dddt)2]} (an envelope conformation) [93].

**Figure 3.** Molecular structure of **5** along the vertical and parallel directions on the molecular plane, with atom labels.

The packing diagrams of **5** are shown in Figure 4. Due to the folded geometry, the columnar structures of the complex were restricted. The shortest Ni–Ni distance was 6.283 Å, which was the length of the *a axis*. The intermolecular S···S contacts shorter than the sum of the van der Waals radius (3.70 Å) were observed between the S(1)–S(1) atoms (3.574 Å) and S(1)–S(4 ) atoms (3.604 Å), which formed a three-dimensional network structure in crystal **5**.

**Figure 4.** Crystal structures of **5** viewed along the (**a**) *a*, (**b**) *b*, and (**c**) *c* axes. Hydrogen atoms are omitted for clarity. The blue dashed lines indicate the intermolecular S···S contacts shorter than the sum of the van der Waals radius (3.70 Å).

The molecular structure of compound **6** is shown in Figure 5. One trans-[Ni(cis-C6 dddt)2] molecule was present in the asymmetric unit of the crystal. The torsion angles around the fused cyclohexylene group of the molecule were 43.79◦, −68.30◦, and −62.81◦ for C(1)-S(3)-C(3)-C(4), C(2)-S(4)-C(4)-C(3), and S(3)-C(3)-C(4)-S(4), respectively. The corresponding torsion angles in the opposite site of the molecule were −45.87◦, −47.04◦, and 66.65◦ for C(9)-S(7)-C(11)-C(12), C(10)-S(8)-C(12)-C(11), and S(7)-C(11)-C(12)-S(8), respectively. The stable chair-type configurations of the cyclohexylene groups were observed. However, the folded conformations of the cyclohexylene groups from the planar [Ni(dddt)2] core were different from those of **L4**, which exhibited larger flexures around the terminal S-C bonds (Figure 1).

**Figure 5.** Molecular structure of **6** along the vertical and parallel directions on the molecular plane with atom labels.

A similar molecular geometry of trans-[Ni(cis-C6-dddt)2] was reported by Bai et al. [94]. However, the packing motif of crystal **6** was significantly different from that of the reported crystal constructed by the centrosymmetric molecular arrangement of trans-[Ni(cis-C6 dddt)2] with an inversion center on the nickel atom. In the case of crystal **6**, a noncentrosymmetric molecular arrangement with a helix axis along the *b* axis formed by the trans-[Ni(cis-C6-dddt)2] molecules was observed (Figure 6). The cyclohexylene rings prevented the formation of stacks of the complexes and intermolecular interactions through the S···S contacts. The shortest intermolecular S···S distance was 3.749 Å between S(1) and S(8). The shortest Ni–Ni distance was 8.030 Å, which was the length of the *a axis*.

One half of the trans-[Ni(cis-C7-dddt)2] molecule was present in the asymmetric unit in Crystal **7** (Figure 7). The twist chair-type configurations of the cycloheptylene groups in **L3** were maintained in the crystals after the coordination reaction of **L3** and the nickel source (Scheme 3). The twist chair-type configurations of the cycloheptylene groups around the terminal S–C bonds in the molecule exhibited larger flexures (Figure 2), with torsion angles around the fused cycloheptylene group of 10.13◦, 68.04◦, and −55.70◦ for C(1)-S(3)-C(3)-C(4), C(2)-S(4)-C(4)-C(3), and S(3)-C(3)-C(4)-S(4), respectively. Figure 8 presents the crystal structure of **7**. The cycloheptylene moieties were in contact along the *c* axis. There was no intermolecular S···S contact, given that the [Ni(dddt)2] cores were completely separated by the steric hindrance of the cycloheptane moieties.

**Figure 6.** Crystal structure of **6** along the (**a**) *a*, (**b**) *b*, and (**c**) *c* axes. Hydrogen atoms are omitted for clarity.

**Figure 7.** Molecular structure of **7** along the vertical and parallel directions on the molecular plane with atom labels.

**Figure 8.** Crystal structure of **7** along the (**a**) *a*, (**b**) *b*, and (**c**) *c* axes. Hydrogen atoms are omitted for clarity.

Figures 9 and 10 present the molecular and crystal structures of **8**. The centrosymmetric crystal was formed by one-half of the trans-[Ni(cis-C8-dddt)2] molecule in the asymmetric unit. The boat-chair-type configurations of the cyclooctylene groups formed in **L4** remained in molecule **6** with torsion angles of 54.74◦, 46.88◦, and −70.84◦ for C(1)-S(1)-C(3)-C(4), C(2)-S(4)-C(4)-C(3), and S(3)-C(3)-C(4)-S(4), respectively. One-dimensional columns along the *a* axis were constructed by ring-over-ring overlaps between the molecules sliding to the molecular longitudinal axis. There were no intercolumnar interactions through the S–S contacts. The shortest distance was 3.775 Å between S(2) and S(3 ) in the column. The columns interacted through the side-by-side intermolecular S···S contacts between S(3) and S(3 ) with a distance of 3.444 Å.

**Figure 9.** Molecular structure of **8** along the vertical and parallel directions on the molecular plane with atom labels.

**Figure 10.** Crystal structure of **8** along the (**a**) *a*, (**b**) *b*, and (**c**) *c* axes. Hydrogen atoms are omitted for clarity. The blue dashed lines indicate the intermolecular S···S contacts shorter than the sum of the van der Waals radius (3.70 Å).

#### *3.2. Electrochemical Properties of* **1**–**4**

Cyclic voltammograms of monoanionic complexes **1**–**4** and (Bu4N)[Ni(dddt)2] in MeCN were obtained (Figure 1). The voltammograms of (Bu4N)[Ni(dddt)2] exhibited two quasi-reversible couples and one irreversible redox couple in the recorded region (Figure 1). The quasi-reversible redox peaks were assigned to [Ni(dddt)2] 0/[Ni(dddt)2] + (*E*1/21 = −1.24 V) and [Ni(dddt)2] −/[Ni(dddt)2] 0 (*E*1/22 = −1.02 V) (Figure 11a). An irreversible oxidation peak was observed at 0.28 V, which indicates a reduction process between the dianionic [Ni(dddt)2] − and monoanionic [Ni(dddt)2] 2− states. The electrochemical features of **1**–**4** were similar to those of (Bu4N)[Ni(dddt)2]. The redox potentials *E*1/21 ([Ni(Cn-dddt)2] 0/[Ni(Cn-dddt)2] +) and *E*1/22 ([Ni(Cn-dddt)2] −Ni(Cn-dddt)2] 0) of **1**–**4** are summarized in Table 6. Potentials *E*1 and *E*2 were correlated to the donor abilities of the complexes. The Δ*E* (= *E*1/22 – *E*1/21) values could be considered a measure of the on-site Coulomb energies [47,64]. Based on the *E*1/21, *E*1/22, and Δ*E* values, the complexes with fused cycloalkanes maintained the donor ability and on-site Coulomb energy of (Bu4N)[Ni(dddt)2].

**Figure 11.** Cyclic voltammograms of (**a**) (Bu4N)[Ni(dddt)2], (**b**) **1**, (**c**) **2**, (**d**) **3**, and (**e**) **4**. Conditions: MeCN (1 × 10−3 M), supporting electrolyte: (Bu4N)(ClO4) (0.1 M), scan rate: 100 mV/s, reference electrode: Ag/Ag+, counter electrode: Pt wire, working electrode: glassy carbon at room temperature.

**Table 6.** Redox potentials *E*1/21/V (0, −1), *E*1/22/V (−1, −2), and Δ*E* (= *E*1/22 − *E*1/21)/V of (Bu4N)[Ni(dddt)2] and Complexes **1**–**4**.

Conditions: MeCN (1 × 10−3 M), supporting electrolyte: (Bu4N)(ClO4) (0.1 M), scan rate: 100 mV/s, reference electrode: Ag/Ag+, counter electrode: Pt wire, working electrode: glassy carbon at room temperature.

#### *3.3. Electronic Absorption Spectra of* **1**–**8**

The electronic absorption spectra of monoanionic complexes **1**–**4** and neutral complexes **5**–**8** in CH2Cl2 were measured. Monoanionic complexes **1**–**4** exhibited a strong and broad absorption band at approximately 1036–1201 nm in the near-infrared region, which

can be attributed to a π–π \* transition between their HOMOs and LUMOs (Table 7) [95,96]. With respect to neutral complexes **5**–**8**, the HOMO–LUMO absorption bands were shifted to the higher energy region (982–1040 nm), which corresponds to the energy gap between HOMO-1 and the HOMOs of the monoanionic complexes due to the weak shoulder absorptions observed at approximately 1000 nm. For example, monoanionic complex **4** exhibited two absorptions at 1201 nm and 1040 nm, which can be attributed to the HOMO–LUMO and HOMO-1 to HOMO gaps, respectively (Figure 12). The HOMO–LUMO gaps of the neutral complexes estimated by the spectra were within the range 1.19–1.26 eV. The spectroscopic behaviors of the complexes were similar to those of other bis(ethylene-1,2-dithiolato) complexes and M(S2C2R2)2 [85–89,93,94,97,98].

**Table 7.** Wavelength at absorption maxima (*λ*max) and absorption coefficients (*ε*) for the π–π\* transitions of **1**–**8** in CH2Cl2.

**Figure 12.** Electronic absorption spectra of (a) **4** (4.82 × 10*−*5 M) and (b) **8** (3.40 × 10*−*5 M) in CH2Cl2 solutions.

## *3.4. Structures and Physical Properties of Radical Cation Crystals* **9** *and* **10** 3.4.1. Molecular and Crystal Structures of **9** and **10**

The electrochemical oxidation of CH2Cl2 solutions, including neutral complex **5** and the corresponding supporting electrolytes (Bu4N)X (X = ClO4 *−* and PF6 *−*), resulted in the crystallization of 2:1 [Ni(cis-C5-dddt)2]2(X) salts. The donor/acceptor ratios of the 2:1 crystals were different from those of the previously reported radical cation crystals based on the [Ni(dddt)2] complex without bulky substituents, constructing the 3:2 crystals of [Ni(dddt)2]3(A)2 (A = AuBr2 *−*, BF4 *−*, ClO4 *−*, HSO4 *−*, and HSeO4 *−* [55,56,99–103]. The crystals of **9** and **10** included one crystallographically independent donor and half of the ClO4 − or PF6 − anions, respectively. Figure 13 and (Supplementary Materials) Figure S1 present the molecular structures of the donors in **9** and **10**. In the case of the radical cation crystals, the cis-[Ni(cis-C5-dddt)2] conformation was formed preferentially, although the corresponding neutral complex exhibited the trans-[Ni(cis-C5-dddt)2] conformation

(Scheme 4). The donors exhibited a square planar coordination around the Ni atoms. Moreover, the bond distances of Ni-S = 2.1438(5)–2.1481(5) Å, S–C = 1.703(2)–1.7077(19) Å, and C=C = 1.406(3)–1.408(3) Å for **9**; and Ni-S = 2.1435(6)–2.1498(6) Å, S-C = 1.702(2)– 1.705(2) Å, and C=C = 1.404(3)–1.414(3) Å for **10** in the NiS4C4 framework were slightly larger than those of the neutral trans-[Ni(cis-C5-dddt)2]. Figure 14 and Figure S2 present the crystal structures of **9** and **10**. In the crystals, similar molecular arrangements of the donors and anions were observed with a two-fold axis on one of the Cl-O and P-F bonds of the anions along the *b* axis, respectively. In **9**, the perchlorate anions were disordered at the two sites by rotation around the two-fold axis. The cis-[Ni(cis-C5-dddt)2] conformation would induce dimerized structures of the donors in **9** and **10**, which differ from the molecular arrangement in the cases of the 3:2 crystals of [Ni(dddt)2]3(A)2 significantly. The dimerized structures of the donors were formed by the S···S contacts (3.665 Å and 3.664 Å for **9** and **10**, respectively), and the dimers were arranged into columnar structures through the S···S contacts (3.682 Å and 3.556 Å for **9** and **10**, respectively) along the *a-c* axis directions in **9** and **10**. Intermolecular side-by-side interactions through the S···S contacts (3.507–3.637 Å and 3.500–3.629 Å for **9** and **10**, respectively) between the columns were observed along the *b* axis, thus providing two-dimensional donor sheets parallel to the *bc* planes. Although the donor molecule is fused with the bulky cyclopentane moieties, the two-dimensional donor sheet arrangements through the S···S contacts preferentially are constructed in the radical cation crystals, which are also observed in the organic radical cation crystals based on the BEDT-TTF and BETS molecules exhibiting metallic and superconducting behaviors [14–18].

**Figure 13.** Molecular structure of **9** along the vertical and parallel directions on the molecular plane with atom labels.

**Figure 14.** Crystal structure of **9** along (**a**) the *a*, (**b**) *b*, and (**c**) *c* axes. Hydrogen atoms are omitted for clarity. The dashed lines indicate sulfur–sulfur distances shorter than the sum of the van der Waals radius (<3.7 Å).

3.4.2. Molecular Orbitals and Energy Band Calculations of **9** and **10**

To reveal the electronic features of the salts, molecular orbitals (MO) and energy band structures were determined using the extended Hückel and tight-binding methods. Figure 15 presents the determined HOMOs and LUMOs of the donor molecules of **9** and **10** in their neutral states. The highly symmetric HOMOs and LUMOs with the nickel *d* orbitals of the donors were in good agreement with the molecular orbitals of the [M(dddt)2] complex calculated based on the first-principles density-functional theory [56–62].

**Figure 15. The** HOMO and LUMO of [Ni(C5-dddt)2].

The calculated overlap integrals (*S*) of the crystals between the HOMOs are summarized in Table 8 with a schematic diagram of their donor arrangements. The symbols a1–b4 indicate directions of intermolecular interactions between the donors. Figure S3 presents the corresponding molecular arrangement of the donor molecules viewed along the end-on direction in the crystal. The significant dimerization of the crystals was observed, given that the face-to-face interactions (a2) were significantly stronger than the other interactions (a1) in the columns. Dominant side-by-side interactions (b1 and b4) connected the dimers, thus forming two-dimensional sheets in the crystals. Figure 16 presents the calculated band structure of **9**, which is similar to that of crystal **10**. Both the upper bands crossed the Fermi level, thus forming the small two-dimensional Fermi surfaces of the crystals.

**Table 8.** Overlap integrals (*S*) between the HOMOs and a schematic diagram of the donor arrange-

*S* **(***×* **103) 9 10** a1 −2.7 −1.9 a2 −10 −10 b1 −6.9 −3.8 b2 −0.14 −0.7 b3 −0.14 −0.7 b4 1.2 −0.3

ments for Crystals **9** and **10**.

**Figure 16.** (**a**) Energy band structure and (**b**) Fermi surface of **9**. The characters *b*\* and *c*\* denote reciprocal lattice axes.

3.4.3. Electrical Conductivities and Magnetic Properties of **9** and **10**

The temperature dependence of the resistivities was measured for single crystals of **9** and **10** K using a standard four-probe direct current (DC) method (Figure 17). The salts exhibited semiconducting behaviors (**9**: *ρ*rt = 0.8 Ω cm and *E*a = 0.09 eV; **10**: *ρ*rt = 4.0 Ω cm and *E*a = 0.13 eV). Although the energy band calculations for **9** and **10** suggested a metallic nature, crystals **9** and **10** exhibited semiconducting behaviors under ambient pressure. The results of the resistivity measurements and the energy band calculations indicate that the crystals forms a Mott insulating state or a spin-singlet state under ambient pres-

sure [104]. In order to reveal the electronic structures of the crystals, temperature dependence of the resistivities under hydrostatic pressures and magnetic susceptibilities of **9** and **10** were measured. The resistivity measurements under various hydrostatic pressures (0.3–1.8 GPa) exhibited slightly smaller activation energies than those under ambient pressure (**9**: *ρ*rt = 0.2 Ω cm and *E*a = 0.07 eV; **10**: *ρ*rt = 1.0 Ω cm and *E*a = 0.12 eV at 1.8 GPa). The temperature dependencies of the magnetic susceptibilities of **9** and **10** were in accordance with the Curie–Wiess law. However, significantly small χ values at 300 K indicate diamagnetic features (χ = 2.9 × 10−5 cm3 mol−1 for **9** and χ = 2.3 × 10−5 cm3 mol−1 for **10**). These results suggest that the crystals formed spin-singlet states between the dimers through the S···S contacts to the b1 direction (Table 8), which is in accordance with their conducting behaviors.

**Figure 17.** Temperature dependence of electrical resistivities of (a) **9** and (b) **10**.

#### **4. Conclusions**

New donor-type nickel–dithiolene complexes based on the [Ni(dddt)2] skeleton fused with bulky cycloalkane substituents were synthesized as new components of molecular conductors. All the neutral crystals were crystallized in cis-[Ni(cis-Cn-dddt)2] conformations with cis-oriented (*R*,*S*) conformations around the cycloalkylene groups due to the [2 + 4] cycloadditions. The flexible cycloalkane moieties in the molecules can induce unique molecular arrangements in their neutral crystals. The three-dimensional network and onedimensional columnar structures were constructed through intermolecular S···S contacts in crystals **5** and **8**. No intermolecular S···S contacts were observed in **6** and **7**. However, [Ni(C6-dddt)2] formed a helical molecular arrangement in the crystal. New cation radical crystals [Ni(C3-dddt)2]2(ClO4 − or PF6 −) with dimerized structures were successfully obtained by electrochemical crystallization, which formed different electronic structures of the [Ni(dddt)2]3(X)2 crystals [55,57,99–103]. The radical cation crystals were insulators due to the spin-singlet states between the dimers through the strong intermolecular S···S contacts. However, the donors with cycloalkane substituents can adjust the proportions of the inter- and intra-dimer interactions through the S···S contacts in their radical cation crystals by modification of the cycloalkane moieties, and allow for the realization of various cation radical crystals with unique donor arrangements by introducing linear, tetrahedral, and octahedral anions. Moreover, neutral crystals are potential candidates for new single-component molecular conductors [58–63].

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/cryst11101154/s1, Figure S1: Molecular structure of **10** along vertical and parallel directions on the molecular plane with atom labels. Figure S2: Crystal structure of **10** along the (a) *a*, (b) *b*, and (c) *c* axes. Hydrogen atoms are omitted for clarity. The dashed lines indicate sulfur–sulfur distances shorter than the sum of the van der Waals radius (<3.70 Å), CIFs: CCDC numbers 2103657–2103665 for **5**–**8**, **9**, and **10**.

**Author Contributions:** Conceptualization, project administration, writing—original draft preparation, writing—review and editing, and funding acquisition, K.K.; investigation and data curation, M.S., S.A., N.H., and T.K.; supervision, T.A., R.K., and J.-i.Y. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by a Grant-in-Aid for Scientific Research (B) [grant number JP18H01956]; and the Research Program of the Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials of the Network Joint Research Center for Materials and Devices [grant number 20214021].

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** We thank Takeo Fukunaga from RIKEN and Yoshitaka Kawasugi from Toho University for technical support related to the X-ray crystallographic analyses and the resistivity measurements under hydrostatic pressures.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**2.9 Control system**

The control system was implemented using the prosthetic hand, Arduino UNO microcontroller, laptop computer, and Myo armband. The Arduino has 14 pins that can be configured as input or output which have the advantage of being able to connect any device that is suitable for transmitting or receiving digital signals of 0 and 5 V. It also has analog inputs and outputs. By means of analog inputs, sensor data can be achieved in the form of continuous variations of a voltage. The analog outputs can normally be used to send control signals in the form of pulse width modulation (PWM) signals.

Labview software was used as a graphical development environment platform, ideal for designing systems with a friendly programming language. It allows to structure and perfect professional works of any system. Communication is made through the serial port between the Arduino and Labview. Through the Arduino UNO card using PWMs, the system controls the DC motors to achieve the different positions and grasps previously established.

Tests were carried out for each one of the actuators to be manipulated and it was verified that the position of each finger for the different types of grasps already proposed to be carried out were those established. For the handling of the robotic hand, a checking was made in the LabVIEW interface. To ensure that the time and angles of the servomotors are correct, tests and measurements were carried out to analyze the inverse and direct kinematics of the prototype, which are analyzed in specific details in the following section.


*Article* **Quantitative Methods to Support Data Acquisition Modernization within Copper Smelters**

**Alessandro Navarra 1,\*, Ryan Wilson 1, Roberto Parra 2, Norman Toro 3,4, Andrés Ross 5, Jean-Christophe Nave 5 and Phillip J. Mackey 6**

Received: 9 October 2020; Accepted: 13 November 2020; Published: 17 November 2020

**Abstract:** Sensors and process control systems are essential for process automation and optimization. Many sectors have adapted to the Industry 4.0 paradigm, but copper smelters remain hesitant to implement these technologies without appropriate justification, as many critical functions remain subject to ground operator experience. Recent experiments and industrial trials using radiometric optoelectronic data acquisition, coupled with advanced quantitative methods and expert systems, have successfully distinguished between mineral species in reactive vessels with high classification rates. These experiments demonstrate the increasing potential for the online monitoring of the state of a charge in pyrometallurgical furnaces, allowing data-driven adjustments to critical operational parameters. However, the justification to implement an innovative control system requires a quantitative framework that is conducive to multiphase engineering projects. This paper presents a unified quantitative framework for copper and nickel-copper smelters, which integrates thermochemical modeling into discrete event simulation and is, indeed, able to simulate smelters, with and without a proposed set of sensors, thus quantifying the benefit of these sensors. Sample computations are presented, which are based on the authors' experiences in smelter reengineering projects.