**2. Soil pollution**

Soil pollution is defined as the build-up in soils of persistent toxic compounds, chemicals, salts, radioactive materials, or disease causing agents, which have adverse effects on plant growth and animal health [1].

Soil is the thin layer of organic and inorganic materials that covers the Earth's rocky surface. The organic portion, which is derived from the decayed remains of plants and animal, is concentrated in the dark uppermost topsoil. The inorganic portion made up of rock fragments, was formed over thousands of years by physical and chemical weathering of bedrock. Productive soils are necessary for agriculture to supply the world with sufficient food [2].

There are many different ways that soil can become polluted, such as:

The most common chemicals involved in causing soil pollution are:

sional and economic divergence between the interests of scientists, stakeholders, authorities, engineers, managers, lawyers, nongovernment organizations (NGOs) and regulators is therefore not unusual. Even neglecting those aspects, a number of unresolved problems exist in the way we currently assess risk and manage the impact of anthropogenic substances in the

This chapter does not intend to present a comprehensive review of all published data from ecological studies at contaminated sites. Instead, the observations from all case studies are used in the discussion and form the basis for the final conclusion. In each case, we try to answer

**5.** Is it possible to make sound field surveys, or do we lack suitable reference situations?

Soil pollution is defined as the build-up in soils of persistent toxic compounds, chemicals, salts, radioactive materials, or disease causing agents, which have adverse effects on plant growth

Soil is the thin layer of organic and inorganic materials that covers the Earth's rocky surface. The organic portion, which is derived from the decayed remains of plants and animal, is concentrated in the dark uppermost topsoil. The inorganic portion made up of rock fragments, was formed over thousands of years by physical and chemical weathering of bedrock. Productive soils are necessary for agriculture to supply the world with sufficient food [2].

**6.** What are the possible soil management methods for the polluted soils?

There are many different ways that soil can become polluted, such as:

terrestrial environment.

the following questions:

**2. Soil pollution**

and animal health [1].

**•** Seepage from a landfill

**•** Solid waste seepage

**•** Discharge of industrial waste into the soil

**•** Rupture of underground storage tanks

**•** Percolation of contaminated water into the soil

**•** Excess application of pesticides, herbicides or fertilizer

The most common chemicals involved in causing soil pollution are:

**1.** What is soil pollution and how it occurs?

4 Environmental Risk Assessment of Soil Contamination

**2.** How to determine the ecological risk assessment of the soil?

**3.** To what extent do soil screening levels (over)estimate risk?

**4.** Do bioassays represent a more realistic risk estimate?

**•** Solvents


*3.3. SEP Co-Treatment Enhances Antioxidant Defenses*

As our results showed a higher neuroprotective activity of SEP co-treatment (1 μM SF, 2.5 μM EGCG, and 0.5 μM PB) compared to the single treatments of 1 μM SF, 2.5, μM EGCG, or 0.5 μM PB, we investigated the ability of SEP co-treatment to modulate the cellular redox state by evaluating GSH levels with an MCB assay. The effect of the different treatments after 24 h on GSH levels is reported in Figure 5. All the treatments were able to significantly increase GSH levels in respect to control cells. In agreement with the viability data, we observed the most effective increase of GSH levels after SEP co-treatment (1 μM SF, 2.5 μM EGCG, and 0.5 μM PB) in comparison to the single treatment of 1 μM SF, 2.5 μM EGCG, or 0.5 μM PB.

**Figure 5.** Antioxidant activity of SF, EGCG, and PB compounds on SH-SY5Y cells. Cells were treated with 1 μM SF, 2.5 μM EGCG, and 0.5 μM PB, and after 24 h GSH levels were evaluated with an monochlorobimane (MCB) assay as reported in Materials and Methods. Data are expressed as a percentage of untreated cells (CTRL). Each bar represents mean ± SEM of three independent experiments. Data were analyzed with a one-way ANOVA followed by the Fisher's test. \* *p* < 0.05 vs. untreated cells; § *p* < 0.05 vs. SEP co-treatment.

#### *3.4. SEP Co-Treatment Modulates Genes Involved in Oxidative Stress Control*

As the previous data showed that SEP co-treatment was significantly more effective compared to the single treatments, we decided to study its ability to modulate cellular antioxidant status. Real-time PCR analysis was employed to investigate the ability of SEP co-treatment to modulate the mRNA level of different antioxidant enzymes. The cDNA was obtained from 3D SH-SY5Y cultures that were co-treated (1 μM SF, 2.5 μM EGCG, and 0.5 μM PB) for 6 h. The 3D cultures were then exposed to 700 μM H2O2 for 1 h prior to lysis (Figure 6). Importantly, SEP co-treatment induced a significant and marked upregulation of heme oxygenase 1 (HO1), NADPH: quinone oxidoreductase 1 (NQO1), glutathione reductase (GR), and thioredoxin reductase (TR) in 3D cultures although with different levels of upregulation (Figure 6). Moreover, SEP co-treatment in the presence of oxidative stress induced a significant upregulation of all tested genes in respect to H2O2-treated cells.

NADPH oxidase (NOX) enzymes have been shown to be a major source of ROS in the brain and to be involved in several neurological diseases [35]. On this basis, we studied the modulatory effect of SEP co-treatment on NOX1 and NOX2 expression using real-time PCR analysis (Figure 7). In the absence of oxidative stress, SEP co-treatment had a strong effect on these enzymes as it significantly reduced NOX1 and NOX2 expression compared to untreated cells. In the presence of oxidative stress (700 μM H2O2), SEP co-treatment significantly reduced NOX1 and NOX2 expression compared to H2O2-treated cells. Of note, SEP co-treatment before peroxide exposure maintained NOX1 levels at a value comparable to control cells.

**Figure 6.** Effect of SEP co-treatment on antioxidant enzyme expression. Cells were co-treated with 1 μM SF, 2.5 μM EGCG, and 0.5 μM PB for 6 h. Oxidative stress was induced with 700 μM H2O2 for 1 h prior to lysis. Real time-PCR was performed to detect heme oxygenase 1 (HO1), NADPH: quinone oxidoreductase 1 (NQO1), glutathione reductase (GR), and thioredoxin reductase (TR) mRNA levels. Data are expressed as relative abundance compared to untreated cells. Each bar represents mean ± SEM of three independent experiments. Data were analyzed with a one-way ANOVA followed by the Fisher's test. \* *p* < 0.05 vs. untreated cells, ◦ *p* < 0.05 vs. H2O2.

**Figure 7.** Effect of SEP co-treatment on NADPH oxidase 1 (NOX1) and NADPH oxidase 2 (NOX2). Cells were co-treated with 1 μM SF, 2.5 μM EGCG, and 0.5 μM PB for 6 h. Oxidative stress was induced with 700 μM H2O2 for 1 h prior to lysis. Real time-PCR was performed to detect NOX1 and NOX2 mRNA levels. Data are expressed as relative abundance compared to untreated cells. Each bar represents mean ± SEM of three independent experiments. Data were analyzed using a one-way ANOVA followed by the Fisher's test. \* *p* < 0.05 vs. untreated cells, ◦ *p* < 0.05 vs. H2O2.

#### *3.5. SEP Co-Treatment is able to Modulate Insulin-Degrading Enzyme (IDE) Gene Expression*

To investigate if SEP co-treatment had other neuroprotective activities besides the antioxidant one, we studied its effect on insulin-degrading enzyme (IDE) expression. IDE plays a significant role in Aβ degradation [36], which is one of the main hallmarks of Alzheimer's disease. Moreover, recent studies have demonstrated that increasing Aβ degradation as opposed to inhibiting synthesis is a more effective strategy for preventing Aβ build-up [37]. In our 3D SH-SY5Y cultures, IDE mRNA levels were downregulated by oxidative stress, but, interestingly, SEP co-treatment (1 μM SF, 2.5 μM EGCG, and 0.5 μM PB) was able to upregulate its expression at levels comparable to untreated cells (Figure 8).

**Figure 8.** Effect of SEP co-treatment on insulin-degrading enzyme (IDE). Cells were co-treated with 1 μM SF, 2.5 μM EGCG, and 0.5 μM PB for 6 h. Oxidative stress was induced with 700 μM H2O2 for 1 h prior to lysis. Real time-PCR was performed to detect IDE mRNA levels. Data are expressed as relative abundance compared to untreated cells. Each bar represents mean ± SEM of three independent experiments. Data were analyzed with a one-way ANOVA followed by the Fisher's test. \* *p* < 0.05 vs. untreated cells, ◦ *p* < 0.05 vs. H2O2.


**Author details**

Henry P. Barham1,2\*, Harry E. Zylicz1,2 and Christian A. Hall1,2

1 Sinus and Nasal Specialists of Louisiana, Baton Rouge, Louisiana, United States of America

2 Rhinology and Skull Base Research Group, Baton Rouge General Medical Center, Baton Rouge, Louisiana, United States of America

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**133**

*Cerebrospinal Fluid Leaks and Encephaloceles DOI: http://dx.doi.org/10.5772/intechopen.91374*

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[10] Schlosser RJ, Bolger WE. Nasal cerebrospinal fluid leaks. The Journal of Otolaryngology. Supplement.

[11] Suwanwela C, Suwanwela N. A morphological classification of sincipital encephalomeningoceles. Journal of Neurosurgery. 1972;**36**:201-211

[13] Zweig JL et al. Endoscopic repair of cerebrospinal fluid leaks to the sinonasal tract: Predictors of success. Otolaryngology and Head and Neck Surgery. 2000;**123**(3):195-201

[12] Wolf G et al. Endoscopic detection of cerebral spinal fistulas with a fluorescence technique. Report of experiences with over 925 cases. Laryngorhinootogie.

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[3] Bleier BS. Comprehensive techniques

in CSF leak repair and skull base reconstruction. Advances in Oto-Rhino-

[4] Bernal-Sprekelsen M, Alobid I, Mullol J, et al. Closure of cerebrospinal

[5] Brown SM, Anand VK, Tabaee A, et al. Role of perioperative antibiotics in endoscopic skull base surgery. Laryngoscope. 2007;**117**(9):1528-1532

[6] Hegazy HM et al. Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea: A meta-analysis. Laryngoscope. 2000;**110**(7):1166-1172

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[8] May M, Levine HL, Mester SJ, et al. Complications of ESS: Analysis of 2,018 patients. Laryngoscope.

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**7. Expression profile for miRNAs in astrocytomas**

in mammals strengthening genetic regulation. At the same time, microRNAs are regulated by oncogenes, tumour-repressing genes, epigenetic mechanisms, genetic abnormalities and defects in the miRNA biogenesis machinery [15]. Each one of these mechanisms may contribute by themselves or, more likely, together, to alter the expression of miRNAs in cancer

The central nervous system of mammals is controlled importantly by genetic regulation mechanisms. MicroRNAs contribute to this regulation; approximately 70% of identified miR-NAs until now are expressed in the brain and some of them are specific to the brain [17]. In recent studies, the pattern of expression for microRNAs was determined and it was shown

A wide variety of microRNAs are in neuronal subtypes with the highest concentration in the brain cortex and cerebellum [19, 20]. In the central nervous system, there are a large number of genes which originate miRNAs and their expression is different depending on the anatomical region. Specific microRNAs for the brain are miR-9, mir-124, miR-125, miR-128 and miR-129 [21–25]. MiR-124 and miR-128 are expressed mainly in neurons, whereas miR-23, miR-26 and miR-29 can be found enriched in astrocytes [10, 26, 27]. In the same way, the expression profile of miRNAs in the development and differentiation of the nervous system in mammals is fundamental, since changes have been documented in their expression when embryo stem cells develop neurogenesis and gliogenesis, which suggests that they may have an important role in differentiation or determination of the cell lineage

Calin et al. were the first ones to find evidence regarding the relation between miRNAs and cancer, demonstrating that miR-15 and miR-16 are located in a mutated region, in over half of chronic lymphocytic leukaemias in B-cells [30]. Several following studies have demonstrated that the expression profiles of several miRNAs are altered in different types of tumours such as glioblastoma, pituitary adenoma, prostate cancer, breast carcinoma, hepatocellular carcinoma, lung carcinoma, colorectal carcinoma, ovarian carcinoma, thyroid and cervical carcinoma, lymphoma and chronic lymphocytic leukaemia [31–35]. For this reason, some of them are considered tumour-suppressive genes or oncogenes [36–38]. Genetic events guiding the development of tumours in the brain are yet unknown; nevertheless, there is evidence which suggests that gliomas may surge starting from a subpopulation of cells within the tumoural mass; these cells have been called 'stem tumour cells', which maintain their ability for renewal and multi-potentiality. MiRNAs are important regulators of the process of differentiation and

that they regulate both development and functionality of the nervous system [9, 18].

**5. Patterns of expression for miRNAs in the brain**

62 Glioma - Contemporary Diagnostic and Therapeutic Approaches

**6. MicroRNAs and their relationship with cancer**

proliferation of stem cells (**Figure 4**) [39–41].

[15, 16].

[9, 14, 22, 28, 29].

Different expression patterns in miRNAs have been described in low- and high-grade astrocytomas including pilocytic, diffuse, anaplastic astrocytomas, and multi-form glioblastoma in adults. In these tumours, miRNAs participate in the cell proliferation, invasion, angiogenesis and differentiation [42, 43]. The first reports are very recent and started with the identification of miRNAs in the GBM in 2005. In this type of tumour, an overexpression of miR-221 was described and proposed as a possible specific marker, whereas miR-128, miR-181a, mir181b and miR-181c were found to be low expression, which probably reflects a loss of expression associated to the lack of differentiation in tumour cells [38]. In that same year, an over-expression of miR-21 in GBM and cell lines was described, comparing it with normal tissue. These effects were related with a reduction of apoptosis and malignant phenotype. On the contrary, the low expression of miR-21 promoted the activation of caspases and apoptosis [44]. Afterwards, in another study, miR-124 and miR-137 were identified, related with the neuronal differentiation in mouse stem cells, derived from a mouse oligodendroglioma and derived of human GBM. Besides, in a cell line of GBM, arrest in the cell cycle after transfecting miR-124 and miR-137 could be observed, which suggests that miR-124 and miR-137 may be target molecules for therapeutic treatments of this illness [44]. These studies suggest that miRNAs participate in multiple biological processes which are characteristic of GBM such as cell differentiation, proliferation, invasion, apoptosis and angiogenesis. Given that miRNAs may promote or limit the development of the tumour, they may be considered as having oncogenic potential or tumour-suppressive activities. MiRNAs analysed in this study and which are considered in the study as having oncogenic potential are miR-15b, miR-21 and miR-221 and the tumour suppressors are miR-124, miR-128, miR-137 and miR-221. Next, each one of them is described [5, 23, 45–48].


5. Conclusion

The purpose of this work was to study a repeatable target production and methods of their noncontact delivery in accordance with the scope of MM-IFE program. Various physics and technology problems accompanying IFE targetfueling development were considered, and approaches to their solution were proposed and experimentally tested partially. Our thermal, mechanical, and levitation modeling (theoretical and experimental) are important tools in planning future experiments on MM-IFE and studying IFE reactor fueling.

A particular interest from scientific and technological points of view in IFE progress deals with a cryogenic target that could be delivered to the center of reaction chamber at significant rates. Therefore, our study is devoted to the IFE target fabrication with focusing on methods, which provide a high rep-rate and cost-effective target production. The top-level requirements necessary to achieve successful target fabrication and injection deal with target material selecting and fuel layer structuring. The following issues are of key importance:

key issues for IFE commercialization. Implementation of MM-IFE program will be useful for working-out and substantiating the technical requirements needed for

Mechanical Mockup of IFE Reactor Intended for the Development of Cryogenic Target Mass…

This work was supported by the RF State Task of the Lebedev Physical Institute of Russian Academy of Sciences, and by the International Atomic Energy Agency

creation of a laser energy power plant.

DOI: http://dx.doi.org/10.5772/intechopen.81518

(Research Contracts No. 20344, 11536, 13871).

Acknowledgements

Author details

Irina Aleksandrova1

Andrei Nikitenko1

77

, Elena Koresheva1

1 Lebedev Physical Institute of the RAS, Moscow, Russia

\*Address all correspondence to<EMAIL_ADDRESS>
provided the original work is properly cited.

2 National Research Center "Kurchatov Institute", Moscow, Russia

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*, Evgeniy Koshelev1

, Boris Kuteev2 and

1. For target mass-production those are:

	- Minimization of time and space for all production steps.
	- Moving targets cooperate all production steps in the FST transmission line that is considered as a potential solution of passing from one-of-a-kind techniques to about 1 million targets per day.
	- Moving targets are the necessary condition for realizing a repeatable target production at required rates and their noncontact delivery at the laser focus.
	- Layers with inherent survival features (fuel layer structuring—the grain size should be scaled back into the nanometer range).
	- Noncontact delivery system.
	- Multiple target protection methods including: (a) outer protective cryogenic layers, (b) metal coatings of different configurations and compositions, (c) nanocoatings for specific applications, and (d) coinjection of a special protective cover ahead of the target, etc.

For the IFE, all techniques must be integrated into an FST transmission line capable of producing about 1 million targets per day. Therefore, further studies are needed on MM-IFE connected to guide other R&D programs and to predict the behavior of IFE targets during their layering, delivery, and transport through the chamber environment. In addition, the MM-IFE allows reducing the cost of developments because it is intended to test the reactor-scaled technologies and to identify Mechanical Mockup of IFE Reactor Intended for the Development of Cryogenic Target Mass… DOI: http://dx.doi.org/10.5772/intechopen.81518

key issues for IFE commercialization. Implementation of MM-IFE program will be useful for working-out and substantiating the technical requirements needed for creation of a laser energy power plant.


**Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies †**

#### **Liwei Lang 1 and Yong Teng 1,2,3,\***

Received: 30 November 2018; Accepted: 8 January 2019; Published: 9 January 2019

**Abstract:** Fibroblast growth factor receptor 4 (FGFR4), a tyrosine kinase receptor for FGFs, is involved in diverse cellular processes, including the regulation of cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. High activation of FGFR4 is strongly associated with the amplification of its specific ligand FGF19 in many types of solid tumors and hematologic malignancies, where it acts as an oncogene driving the cancer development and progression. Currently, the development and therapeutic evaluation of FGFR4-specific inhibitors, such as BLU9931 and H3B-6527, in animal models and cancer patients, are paving the way to suppress hyperactive FGFR4 signaling in cancer. This comprehensive review not only covers the recent discoveries in understanding FGFR4 regulation and function in cancer, but also reveals the therapeutic implications and applications regarding emerging anti-FGFR4 agents. Our aim is to pinpoint the potential of FGFR4 as a therapeutic target and identify new avenues for advancing future research in the field.

**Keywords:** FGFR4; FGF19; gene regulation; cancer signaling; anticancer

#### **1. Introduction**

Fibroblast growth factor receptors (FGFRs) have been found to play a vital role in tumorigenesis and cancer progression through increased cell proliferation, metastasis, and survival [1,2]. Compared with the other three FGFR family members, the signaling pathways and mechanisms of FGFR4 involved in cancer development are less characterized. The expression of FGFR4 is strictly regulated in human adult organs and tissues after fetal development, suggesting it perhaps has a particular relevance to tissue functions. Recently, elevated FGFR4 has been tightly correlated with cancer development and progression, making it an attractive target to develop novel and effective anticancer therapeutics. More efforts have been focused on developing selective inhibitors to target FGFR4, which show particular promise as an anticancer monotherapy or an adjunct treatment.

#### **2. Molecular Characters of FGFR4 and Its Ligands**

#### *2.1. The Molecular Structure of FGFR4*

FGFR4 is one of four family members harboring tyrosine kinase (TK) domains. The human *FGFR4* gene is located on the long arm of chromosome 5 (5q 35.1). The *FGFR4* gene consists of 18 exons and has five transcript variants with three of them encoding the FGFR4 isoform 1 (Figure 1A) [3]. The 802 amino acid (aa) core region in the FGFR4 protein contains four parts, signal peptide (1–21 aa), extracellular region (22–369 aa), transmembrane region (70–390 aa), and the intracellular region (391–802 aa) (Figure 1B). Similar to the other three FGFR members, the extracellular region of FGFR4 consists of three immunoglobulin-like domains (IgI, IgII, and IgIII), which are essential for specific ligand-binding. IgI is located in 50–107 aa with a length of 97 aa. IgII and IgIII are located in order in 157–241 aa and 264–351 aa. Compared with the other three family members, FGFR4 does not have a splice variant on the IgIII [4]. Several ligand binding sites have been identified, such as 273, 278–280, 309–310, 316, and 337 aa. The TK domains locate in the C terminal from 454–767 aa with several tyrosine (Y) for autocatalysis, such as Y642, Y643, and Y764 (Figure 2).

**Figure 1.** The molecular structure of FGFR4. (**A**) The illustration of FGFR4 with mRNA structure. The transcript variant 1 of FGFR4 contains 18 exons and encodes isoform 1 of FGFR4 protein with the main function domains. (**B**) The main domains of FGFR4 with the corresponding function.

#### *2.2. The Ligands of FGFR4*

FGFs are a family of 22 different proteins in vertebrates and are classified into seven subfamilies including FGF1, FGF4, FGF7, FGF8, FGF9, FGF19 ligand subfamily, and FGF11 subfamily [5]. The members of FGF11 subfamily are not ligands of FGFRs and are known as FGF homologous factors [5], while all other six subfamilies work as ligands to bind with FGFR4 (Figure 2) [6]. In other words, ten canonical FGF subfamily members (FGF1, FGF2, FGF4, FGF6, FGF7, FGF8, FGF9, FGF16, FGF17, and FGF18) and three FGF19 subfamily members (FGF19, FGF21, and FGF23) have the potential to bind FGFR4 (Figure 2). Canonical FGFs bind to and activate FGFR4 with heparin/heparin sulfate (HS) [7], while FGF19 subfamily members need β-klotho (KLB) as a co-receptor to bind with FGFR4. FGF1, FGF4, and FGF8, have a higher affinity to bind FGFR4 than other canonical FGFs. Most importantly, FGF19, as an endocrine ligand, has a more specific selective affinity to FGFR4 than other FGFR members [8,9].

**Figure 2.** The FGF/FGFR4 signal axis. The signal transduction mediated by the FGF/FGFR4 axis is extremely complex, which includes PKC, ERK1/2, AKT, Src, and GSK3β signaling cascades. The homodimer of FGFR4 forms when binding to either canonical FGF subfamily members (FGF1, FGF2, FGF4, FGF6, FGF7, FGF8, FGF9, FGF16, FGF17, and FGF18) or FGF19 subfamily members (FGF19, FGF21, and FGF23). Heparin or heparin sulfate is required for the binding of canonical FGF subfamily members to FGFR4, whereas KLB acts as a co-receptor of FGFR4 to facilitate FGFR4 interacting with FGF19 subfamily members. When FGFR4 forms protein complexes with FGFs, it can be phosphorylated on three main tyrosine residues: Y642, Y643, and Y764.

#### *2.3. The Physiologic Functions of FGFR4*

As an important mediator of homeostasis in the liver, FGFR4 function is required for the maintenance of both lipid and glucose metabolism under normal dietary conditions, in addition to its established role in cholesterol [10]. Particularly, FGFR4 activated by endocrine FGF19 represses the gluconeogenesis and stimulates of glycogen and protein synthesis in hepatocytes [11]. The liver-protective effect of FGFR4 becomes even clearer in the model of carbon tetrachloride-induced liver damage, where more significant liver fibrosis was observed in FGFR4 knock-out compared with wild-type (wt) mice [12]. The importance of FGFR4 in controlling bile acids was also established. It has been reported that bile acids secretion and cholesterol metabolism are regulated by FGF19 through binding to FGFR4 in physical activity [13]. It is worth mentioning that the FGF6/FGFR4 pathway plays important role in myoblast differentiation and myotube regeneration [14,15].

#### **3. The Genetic Alterations of FGFR4 Gene in Cancer**

The high expression levels of *FGFR4* can be detected during fetal human and mouse embryonic development. However, deletion of *FGFR4* does not lead to developmental abnormalities in adult mice only with changed cholesterol metabolism and elevated bile acids [16,17]. The expression of FGFR4 is dramatically decreased although it still consistently expresses in several organs, especially in the liver. Gene alterations of FGFRs, including amplification, translocation, and mutation of gain of function, have been linked to tumorigenesis and cancer progression in solid and hematological malignancies. Recently, one study was conducted to evaluate the alterations of FGFR genes in a variety of cancer types [18], which showed that gene alterations of FGFRs occurred in 7.1% of 4853 solid tumors, with the majority being gene amplification (66% of the aberrations), followed by mutations (26%) and translocations (8%). Amplification was the predominant type of alteration for the *FGFR4* gene, accounting for 78% of all FGFR4 gene alterations. Interestingly, the amplified FGFR4 gene was identified in 10% of breast cancer, which more frequently harbors estrogen- and progesterone-receptor with lymph-node metastases [11]. Unlike FGFR1, the translocation of FGFR4 is very rare in human cancers [18]. Two point mutations in the TK domains of the *FGFR4* gene, K535 and E550, have been identified in rhabdomyosarcoma [19]. Another activating point mutation in *FGFR4* gene (Y367C) inducing constitutive FGFR4 dimerization, has been found in MDA-MB-453 breast cancer cells [20]. Although the gene alteration is relatively low, FGFR4 overexpression has been reported in many types of cancer. Increased FGFR4 mRNA expression has been detected in one-third of hepatocellular carcinoma (HCC) [21]. In another study, elevated FGFR4 mRNA levels were detected in 32% of breast cancer samples [22]. FGFR4 overexpression is also observed in 64% (153/238) of oropharyngeal squamous cell carcinoma and 41% (87/212) of oral squamous cell carcinoma [23]. Overexpressed FGFR4 has also been found in pancreatic carcinomas and derived cell lines, which are mediated by an intronic enhancer activated by hepatic nuclear factor 1 alpha [24]. Additionally, highly FGFR4 expression was detected in rhabdomyosarcoma [19].

As a specific ligand of FGFR4, FGF19 can bind and active FGFR4 with the co-receptor KLB. FGFR4 consistently activated by amplified FGF19 has been identified in several types of cancer. The *FGF19* gene is located on chromosome 11q13.3, a region commonly amplified in human cancer.  For example, the frequency of the amplified *FGF19* gene is as high as 15% in HCC [26]. Moreover, compared with adjacent normal liver tissues, HCC tissues have significantly elevated mRNA levels of FGF19 [30], suggesting the increased mRNA expression is tightly associated with its amplification. A similar tendency was also identified in HNSCC where FGF19 amplification corresponds with an increased dependency upon FGF19–FGFR4 autocrine signaling [31].

#### **4. Mechanisms and Functions of FGFR4 in Cancer Development and Treatment**

Accumulating observations indicate that the FGFR4 plays vital roles for cancer development, especially for those harboring *FGF19* amplification. Unlike other family members, the mechanisms and functions of FGFR4 are still poorly characterized at the molecular level in cancer development and progression. Here, the novel observations of mechanisms and functions about oncogenic FGFR4 signaling in cancer development and progression have been summarized and discussed.

#### *4.1. FGFR4-Mediated AKT and ERK Signaling Cascades Promote Cancer Development*

The MAPK-ERK and PI3K-AKT signaling are two main pathways regulated by the FGF/FGFR protein complexes. After binding FGFs with HS or KLB, FGFR4 will be activated through autophosphorylation and forms a homodimer (Figure 2). FGFR4 also has the potential to form a heterodimer receptor with other family members, especially with FGFR3 [32,33]. Mechanistic studies showed that phosphorylated FGFR4 recruits and phosphorylates two important intracellular targets, phospholipase γ (PLCγ) and FGFR substrate 2 (FRS2) [4]. MAPK then can be stimulated by activated protein kinase C (PKC) through PLCγ. Meanwhile, the MAPK and PI3K-AKT pathway can be triggered by activated FRS2 through recruitment of growth factor receptor bound 2 (GRB2) (Figure 3) [4]. Upregulated activity of AKT and ERK1/2 leads to enhanced cell proliferation and survival in HCC upon the activation of FGF19/FGFR4 signaling (Figure 3) [34–36].

**Figure 3.** The signal transduction cascades of FGF19/FGFR4 in cancer development and progression. In cancer cells, once FGFR4 receives the extracellular signal from FGF19, it activates many downstream pathways, including PI3K-AKT, MEK-ERK, and GSK3β-β-catenin, leading to increased tumor-promoting activities. FGFR4 activation can be blocked by two non-genetic strategies, using either monoclonal antibodies (e.g., U3-1798) or selective small-molecule inhibitors (e.g., BLU9931, H3B-6527 and FGF401).

*FGF19* is more highly expressed in the breast cancer tissue than the adjacent normal tissue [37], and co-expression of *FGFR4* and *FGF19* accounts over 28% primary breast cancer [38]. AKT phosphorylation is strongly associated with co-expression of *FGF19* and *FGFR4*, which can be blocked with FGF19 antibody (1A6) or siRNA-mediated silencing of *FGF19* in breast cancer cells [27].  Inactivation of FGFR4 by its inhibitor BLU9931 significantly attenuates FGF19-induced tumor-promoting activity, suggesting interruption of FGFR4 function is sufficient to affect FGF19-driven breast cancer [37].

Our recent study demonstrates that *FGF19* amplification and overexpression are associated with a poorer overall survival rate for HNSCC patients, provoking FGFR4-dependent ERK/AKT-p70S6K-S6 signaling activation to increase HNSCC cell proliferation [31]. Blocking activation of FGFR4 by small hairpin RNAs (shRNAs) or BLU9931, not only attenuates FGF19-induced ERK1/2 and AKT activation, but also abrogates its ability to induce cell proliferation [31]. FGFR4-induced activation of ERK1/2 and AKT pathways was also correlated with increased cell proliferation and survival in colorectal cancer (CRC) [39].

#### *4.2. The FGF19–FGFR4 Axis Promotes Epithelial-Mesenchymal Transition (EMT) to Accelerate Metastasis*

The FGF19–FGFR4 axis has been linked to metastasis and poor survival [26]. FGFR4 is predominantly expressed in the liver and responsive for FGF19 stimulation to regulate cholesterol metabolism. There is no doubt that elevated FGF19–FGFR4 signaling is associated with HCC progression, especially for metastasis [26,40]. Our research team has demonstrated that the FGF19/FGFR4 axis facilitates HCC cell EMT through upregulating GSK3β-β-catenin signaling and consequently increases HCC metastasis (Figure 3) [30]. Recently, a vital role of FGFR4 was found in CRC metastasis. Activated FGFR4 phosphorylates AKT, ERK1/2, and Src, leading to increased CRC cell invasion. Silencing FGFR4 reduces adhesion, migration, and invasion of CRC cells [39]. Further study shows that depletion FGFR4 by CRISPR-Cas9 results in the morphological changes and reduced metastasis ability, accompanied by upregulation of E-cadherin and downregulation of Snail and other EMT mediators [39]. Moreover, FGFR4-GSK3β-β-catenin is also elucidated in CRC metastasis. Elevated expression of *Forkhead box C1* (*FOXC1*) is tightly correlated with metastasis of CRC, and FGFR4 is the main target of this gene [41]. BLU9931, the specific inhibitor of FGFR4, can inhibit the activation of GSK3β/β-catenin induced by *FOXC1* overexpression in vitro and metastatic colonization of CRC in vivo [41].

#### *4.3. FGFR4-Associated Chemotherapy Resistance in Cancer*

Cancer cells may develop a mechanism that inactivates the drug which represents the main obstacle for cancer treatment. It can be achieved by cancer cells through different mechanisms, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and EMT [42]. The FGF19–FGFR4 axis has participated in chemotherapy resistance in several types of cancers. The expression levels of FGFR4 are significantly increased in doxorubicin-resistant breast cancer clones [43]. Moreover, FGFR4 overexpression has been detected in those insensitive breast cancer cell lines to doxorubicin [43]. Silencing *FGFR4* with small interfering RNA (siRNA) in chemo-resistant clones increases their sensitivity to doxorubicin. Furthermore, inhibition of FGFR4 with an antagonistic antibody also enhances the sensitivity of endogenously FGFR4-expressing cell lines to doxorubicin. Inhibition of apoptosis by FGFR4 is the main mechanism of doxorubicin resistance in breast cancer [43]. Bcl-xL, an anti-apoptotic protein, is upregulated by FGFR4 via MAPK cascade and responsive for the increased resistance to doxorubicin [43]. Other studies indicate that upregulation of FGF19–FGFR4 signaling increases drug resistance to doxorubicin in basal-like breast cancer [27]. Inactivation of FGFR4 signaling by an anti-FGF19 antibody or siRNA-mediated *FGF19* gene silencing, can sensitize FGFR4+/FGF19+ breast cancer cells to doxorubicin treatment [27]. Increased sensitivity to 5-fluorouracil (5-FU) or oxaliplatin treatment has also been observed after *FGFR4* silencing in CRC cells [44].

As a multiple TKI, sorafenib is an efficient target therapy agent to treat HCC. However, sorafenib is always restricted to continuous administration by occurring drug resistance with unknown mechanisms [45,46]. Recently, our study shows that activation of the FGF19–FGFR4 axis is one of the main mechanisms for sorafenib resistance in the treatment of HCC [47]. The outbalanced oxidative stress induced by reactive oxygen species (ROS) plays a pivotal role in apoptosis [48]. Mechanistically, sorafenib induces ROS-associated apoptosis, but this can be suppressed by *FGF19* overexpression in HCC cells. The FGF19–FGFR4 axis has the potential to assist HCC cancer cells to escape apoptosis in sorafenib treatment through suppression of ROS. *FGFR4* knockout increases the sensitivity to sorafenib treatment in HCC cells, accompanied by enhanced cell apoptosis [47]. Silencing the *FGF19* gene or inactivating FGFR4 with the FGFR-pan inhibitor ponatinib, significantly increases the sensitivity to sorafenib in sorafenib-resistant HCC cells, with induced apoptosis and accumulated ROS generation [47]. Additionally, a similar phenomenon is also observed in young adult mouse colonic epithelial cells. Upregulating FGF19–FGFR4 signaling significantly reduces ROS-mediated apoptosis caused by H2O2 through blocking the caspase-3 pathway [49], which also prevents prostate cancer cells from apoptosis in TNFα treatment [50].

#### **5. Develop Specific FGFR4 Inhibitors Targeting Cancer Harboring Elevated FGF19/FGFR4 Signaling**

As a promising target, FGFR4 attracts intensive pharmaceutical and academic attention to develop novel target therapy against cancers driven by FGFR4. Three strategies have been developed to target FGFR4, including neutral antibodies, antisense oligonucleotides, and small molecule inhibitors. Two monoclonal neutralizing antibodies of FGFR4, LD-1, and U3-1784, have been developed to competitively targeting extracellular Ig domains of FGFR4. The therapeutic efficacy of U3-1784 is currently being evaluated in Phase I clinical trials for the treatment of HCC and other advanced solid tumors [51] (Table 1 and Figure 3). As an antisense oligonucleotide targeting FGFR4 mRNA, ISIS-FGFR4RX has entered a Phase I clinical trial for obesity (NCT02476019). However, the potential anticancer activity of ISIS-FGFR4RX has not been reported.

Comparing two strategies above, targeting FGFR4 using small-molecule inhibitors is more feasible and can be developed through structure-guided drug design. Not surprisingly, multi-targeted tyrosine kinase inhibitors (mTKIs) can be used to inactivate FGFR4 by disrupting ATP binding in its TK domains. The anticancer activity of many mTKIs, including lenvatinib and ponatinib, have been tested on FGFR-driven solid tumors in animals or in clinical trials (Table 1) [52–54]. However, the limited selective activity of mTKIs on FGFRs induces less efficiency and increases side effects in these treatments. Therefore, pan-FGFR inhibitors are developed and are being evaluated in clinical trials to treat cancers driven by abnormal FGFR pathways. Most of these inhibitors target ATP binding pocket in the TK domains of FGFRs through reversible or covalent bonds. For example, ponatinib can impede the autophosphorylation activity of FGFRs by binding to the hinge region of FGFRs and block the ATP-binding cassette motif [5]. As such, ponatinib has the great potential to inhibit the enzyme activity of FGFRs which are always hyperactive in cancer cells. Other inhibitors in this category include ATP-competitive inhibitors NVP-BGJ398 [55] and AZD4547 [56], ATP-binding pocket inhibitor LY2874455 [57], and FGFRs-FIIN-3 which generates a covalent bond with a conserved cysteine located in the ATP binding site (Table 1) [58]. However, the low specificity of these pan-FGFR inhibitors to FGFR4 cannot sufficiently suppress the oncogenic FGFR4 signaling. For example, the IC50 of AZD4547 on FGFR4 is over 100-fold higher than other FGFR members [59]. Moreover, inevitable on-target toxicities and off-target activity resulting from the use of nonspecific FGFR inhibitors lead to several adverse effects such as soft-tissue mineralization and hyperphosphatemia [60]. Such disadvantages eventually limit their usage in cancer patients.

Compared with other FGFR family members, FGFR4 is more specifically expressed in the liver and several other organs for bile acid secretion and cholesterol metabolism. Therefore, the generation of more specific inhibitors which only abolish FGFR4 can improve FGFR4 sensitivity and overcome the drawbacks of pan-FGFR inhibitors. BLU9931 is the first selective FGFR4 inhibitor for the treatment of HCC with an activated FGFR4 signaling pathway [61,62]. As a novel irreversible kinase inhibitor, BLU9931 creates a covalent bond with Cysteine 552 near the ATP-binding site that is only present in FGFR4 among FGFRs [62]. BLU9931 can effectively inhibit HCC tumor harboring elevated FGF19–FGFR4 axis in vivo. Moreover, BLU9931 also displays the potent anticancer ability in breast cancer, CRC, and HNSCC with upregulated FGF19–FGFR4 signaling [37,41]. BLU554 was derived from BLU9931 with improved pharmaceutical properties, which is now in Phase I clinical trial to treat HCC with elevated FGF19–FGFR4 axis (NCT02508467) (Table 1) [63]. H3B-6527 is another selective FGFR4 inhibitor currently in clinical trials for HCC treatment (Table 1). H3B-6527 also targets Cysteine 552 through forming a covalent bond near the ATP binding site of FGFR4, and it exhibits an inhibitory effect on FGFR4 activation in FGF19-driven HCC in vitro and in vivo [64]. By studying a panel of 40 HCC cell lines and 30 HCC patient-derived xenograft models, the expression levels of FGF19 are implicated as a predictive biomarker for H3B-6527 response [64]. Moreover, the combination of H3B-6527 with the CDK4/6 inhibitor palbociclib has a superior effect on the repression of tumors in a xenograft model of HCC [64]. FGF401 is another selective FGFR4 inhibitor, which is under investigation in a phase I/II study to treat HCC with FGFR4 and KLB expression (NCT02325739) [65]

(Table 1). FGF401 is evaluated to treat HCC as the single use or combined with a humanized anti-PD1 IgG4 antibody PDR001 [65]. These novel FGFR4-targeting therapies provide a novel and promising approach which could potentially be developed into a therapeutic strategy to combat cancer.

**Table 1.** Clinical trials of FGFR4 inhibitors for cancer treatment.

#### **6. Conclusions**

Increasing evidence indicates that upregulation of FGF19–FGFR4 signaling plays an essential role in tumorigenesis and cancer progression. FGFR4 has been proven as an attracted target to develop a novel therapy for the subgroup of cancers associated with the FGF19–FGFR4 pathway. Given that overexpression of FGFR4 significantly correlates with EpCAM, a marker of hepatic cancer stem cells, within the fatty liver-steatosis-cirrhosis-HCC sequence [66], FGFR4 may have the ability to regulate cancer stem cells and lead to chemoresistance in HCC or other cancers. Gaining these insights will improve our comprehensive understanding of the role of FGFR4 in cancer development and treatment. Recently, more specific inhibitors targeting FGFR4 have been developed and evaluated, which are demonstrating promise as a single agent therapy or in combination with other anticancer agents. Thus, there is no doubt that FGFR4-targeting inhibitors offer the most immediate prospects of reducing cancer mortality rate. Perhaps, we can design stapled peptides [67] to incorporate the hydrophobic staple at the interface of FGF19–FGFR4 binding sites, which would increase the specificity of signal targeting compared to the FGFR4 inhibitors that are commercially available. Although the critical role of FGFR4 in metastasis has been demonstrated in animal models of several cancers, prospective studies are warranted to provide evidence regarding the therapeutic efficacy of FGFR4 inhibitors in clinical metastatic cancers.

#### **Abbreviation**

**Author Contributions:** Writing—L.L., Y.T.; Review and editing—Y.T. **Funding:** This research received no external funding. **Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

© 2019 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 (http://creativecommons.org/licenses/by/4.0/).

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**Acknowledgements**

The research underpinning the present study has been supported by the work of Prof. Paolo Marino and of Dr. Giusi Iammarino of the former Institution Microbiology of the University of Naples Federico II, faculty of Agronomy. The author is grateful to the Acerra Wastewater Treatment Plant Laboratory, which provided the biological mass, along with its accurate characterization.


**INFLAMMATORY DISEASES – A MODERN PERSPECTIVE**

Edited by **Amit Nagal**

**INTECHOPEN.COM**

http://dx.doi.org/10.5772/2437 Edited by Amit Nagal

#### **Contributors**

Ken-Ichiro Inoue, Amit Nagal, Kamel Hamzaoui, Eya Bouali, Christopher Jackson, Meilang Xue, Véronique Freund-Michel, Bernard Muller, Nelly Frossard, Susan Costantini, Giovanni Colonna, Ankush Sharma, Jelena Milašin, Antonio Ferrante, Charles Hii, Jesus Bellido Casado, Jade Forwood, Crystall Swarbrick, Noelia Roman, Nadja Berger, Janine Cooney, Nicole Roy, Emma Bermingham, Warren McNabb

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**Vibrational Spectroscopic Study on Lubrication and Corrosive Wear Mechanisms of Imidazolium Based Ionic Liquids**

Seiya Watanabe, Miki Nakano, Koji Miyake, Chiharu Tadokoro and Shinya Sasaki

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/59132

#### **1. Introduction**

Ionic liquids are liquid (molten) salts, distinguished by having melting points below room temperature [1]. The favorable properties of ionic liquids such as high thermal stability, low volatility, non-flammability, low melting point, and broad liquid range make them suitable for use in superior lubricants and additives. Moreover, the physical and chemical properties of ionic liquids can be tailored by changing the structure and type of the cation or anion. However, there are difficulties hindering the practical use of ionic liquids as lubricants. One of the most critical problems is that almost ionic liquids undergo a complex tribochemical reaction with metal surfaces [2-4]. In addition, the ionic liquid forms a characteristic structure at solid-liquid interface; the effect of this interfacial structure on the tribological properties has not been assessed because of the difficulties associated with the analysis [5-8]. Hence, for the molecular design of ionic liquids that can be used as lubri‐ cants, the mechanisms of corrosive wear and lubrication should be clarified. In this respect, developing an in situ technique that enables direct observation of the ionic liquid mole‐ cule under lubricating conditions is an important step toward understanding the complex molecular behavior of ionic liquids.

In this paper, we explain our recent research at attempting to clarify the mechanisms of corrosive wear and lubrication of ionic liquids. Specifically, we examined the corrosive wear induced by a tribochemical reaction via Fourier transform infrared (FT-IR) spectroscopy and the lubrication mechanism via sum frequency generation (SFG) spectroscopy.

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

### **2. Effect of water in ionic liquid on corrosive wear – Analysis by FT-IR spectroscopy [3,9]**

#### **2.1. Experimental**

In general, the corrosive wear caused by an ionic liquid is attributed to the reaction between the halogen species in the anion part and water which is a common contaminant in ionic liquids. We used the hygroscopic 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([BMIM] OTf) as a model ionic liquid and investigated the effect of water on corrosive wear against AISI 52100, which is a typical friction material. We used an FT-IR instrument equipped with a pin-on-disk tribometer for the analysis, with a calcium fluoride disk and an AISI 52100 pin with a diameter of 8 mm. The weight of the pin was 36 mN. This apparatus helped us obtain molecular information of the ionic liquid film sandwiched between the pin and the disk. To investigate the molecular behavior of water contained in the ionic liquid, the IR spectrum in the static state (without disk rotation) was mainly examined.

#### **2.2. Results and discussion**

Figure 1(a) shows time variations in the IR spectrum of the ionic liquid under static conditions (humidity: 4.6–6.9 g/m3 , relative humidity: 20–30%). The test duration was 72 h. Figure 1(b) shows the surface image of the pin after the test. The IR spectra recorded over the test period showed that the ionic liquid absorbed water from the air. At the same time, it is important to note that two mixture phase of water were observed. The O-H stretching mode at ~3506 cm-1 and ~3582 cm-1 increased from the start of the test until 4–5 h had elapsed. However, after 5– 7 h, a new peak at 3400 cm-1 was observed, and the intensity of this peak started to increase.

IR analysis focusing on water in the ionic liquid was previously carried out by Cammarata et al. Figure 2 shows the IR spectrum of water mixed with different hydrophilic ionic liquids, from that study. The peaks for the O-H stretching mode at ~3506 cm-1 and ~3582 cm-1 were found to be attributed to "free water," and this state corresponded to water molecules showing weak interactions with the anion [10]. The peak of the O-H stretching mode at 3400 cm-1 was attributed to the three-coordinate integrated water state, that is, "liquid-like water," and this state corresponded to water molecules interacting with one another to form a network structure [11].

From the above results, it was inferred that water is initially absorbed into the ionic liquid as free water, and after the elapse of 5–7 h, the amount of liquid-like water increases. Figure 1(b) shows the optical image of the pin surface after the test, indicating severe corrosion. On the other hand, when the test was stopped before the observed increase in the amount of liquidlike water (Figure 3), corrosion did not occur at the pin surface. From these results, it is evident that there is some relationship between the amount of liquid-like water and corrosion.

Subsequently, to clarify the relationship between sliding, corrosion, and the generation of liquid-like water, we attempted to investigate the water behavior in the rotating state. Tests were conducted at 10 rpm of disk rotation from the test start. The test duration was 8 h, and Vibrational Spectroscopic Study on Lubrication and Corrosive Wear Mechanisms of Imidazolium Based Ionic Liquids http://dx.doi.org/10.5772/59132 547

Figure 1. Static<\$%&?>condition<\$%&?>test<\$%&?>for<\$%&?>72<\$%&?>hours<\$%&?>at<\$%&?>4.6<\$%&?>~<\$%&?>6.9<\$%&?>g/m3<\$ %&?>(a)<\$%&?>Time<\$%&?>dependent<\$%&?>change<\$%&?>of<\$%&?>FT-IR<\$%&?>spectra<\$%&?>of<\$%&?>[BMIM]OTf,(b)<\$%&?> **Figure 1.** Static condition test for 72 hours at 4.6 ~ 6.9 g/m3 (a) Time dependent change of FT-IR spectra of [BMIM]OTf, (b) Pin surface image after the test [9]

Pin<\$%&?>surface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>[9]

**Figure 2.** ATR-IR spectra of water in six ionic liquids [10]

**2. Effect of water in ionic liquid on corrosive wear – Analysis by FT-IR**

In general, the corrosive wear caused by an ionic liquid is attributed to the reaction between the halogen species in the anion part and water which is a common contaminant in ionic liquids. We used the hygroscopic 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([BMIM] OTf) as a model ionic liquid and investigated the effect of water on corrosive wear against AISI 52100, which is a typical friction material. We used an FT-IR instrument equipped with a pin-on-disk tribometer for the analysis, with a calcium fluoride disk and an AISI 52100 pin with a diameter of 8 mm. The weight of the pin was 36 mN. This apparatus helped us obtain molecular information of the ionic liquid film sandwiched between the pin and the disk. To investigate the molecular behavior of water contained in the ionic liquid, the IR spectrum

Figure 1(a) shows time variations in the IR spectrum of the ionic liquid under static conditions

shows the surface image of the pin after the test. The IR spectra recorded over the test period showed that the ionic liquid absorbed water from the air. At the same time, it is important to note that two mixture phase of water were observed. The O-H stretching mode at ~3506 cm-1 and ~3582 cm-1 increased from the start of the test until 4–5 h had elapsed. However, after 5– 7 h, a new peak at 3400 cm-1 was observed, and the intensity of this peak started to increase.

IR analysis focusing on water in the ionic liquid was previously carried out by Cammarata et al. Figure 2 shows the IR spectrum of water mixed with different hydrophilic ionic liquids, from that study. The peaks for the O-H stretching mode at ~3506 cm-1 and ~3582 cm-1 were found to be attributed to "free water," and this state corresponded to water molecules showing weak interactions with the anion [10]. The peak of the O-H stretching mode at 3400 cm-1 was attributed to the three-coordinate integrated water state, that is, "liquid-like water," and this state corresponded to water molecules interacting with one another to form a network

From the above results, it was inferred that water is initially absorbed into the ionic liquid as free water, and after the elapse of 5–7 h, the amount of liquid-like water increases. Figure 1(b) shows the optical image of the pin surface after the test, indicating severe corrosion. On the other hand, when the test was stopped before the observed increase in the amount of liquidlike water (Figure 3), corrosion did not occur at the pin surface. From these results, it is evident that there is some relationship between the amount of liquid-like water and corrosion.

Subsequently, to clarify the relationship between sliding, corrosion, and the generation of liquid-like water, we attempted to investigate the water behavior in the rotating state. Tests were conducted at 10 rpm of disk rotation from the test start. The test duration was 8 h, and

, relative humidity: 20–30%). The test duration was 72 h. Figure 1(b)

in the static state (without disk rotation) was mainly examined.

**spectroscopy [3,9]**

546 Ionic Liquids - Current State of the Art

**2.2. Results and discussion**

(humidity: 4.6–6.9 g/m3

structure [11].

**2.1. Experimental**

Figure 3. .<\$%&?>Static<\$%&?>condition<\$%&?>test<\$%&?>for<\$%&?>5<\$%&?>hours<\$%&?>at<\$%&?>6.0<\$%&?>g/m3<\$%&?>(a)<\$%& ?>Time<\$%&?>dependent<\$%&?>change<\$%&?>of<\$%&?>FT-IR<\$%&?>spectra<\$%&?>of<\$%&?>[BMIM]OTf,(b)<\$%&?>pin<\$%&?>s **Figure 3.** Static condition test for 5 hours at 6.0 g/m3 (a) Time dependent change of FT-IR spectra of [BMIM]OTf,(b) pin surface image after the test [9]

urface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>[9]

the humidity was 3.8 g/m3 (relative humidity: 20%). Time variations in the IR spectrum are shown in Figure 4(a). During the test period, the O-H stretching mode corresponding to liquidlike water was not observed, indicating that water is absorbed into the ionic liquid as free water. Corrosion was observed from the surface image after the test (Figure 4(b)), even though liquid-like water was not observed. The reason for this result is because scratch scars induced by sliding were created at the pin surface. The scars gave rise to a topical potential difference, consequently resulting in a galvanic corrosion environment. The absence of liquid-like water under rotating conditions was rationalized as follows: even if liquid-like water was produced near the frictional surface, it was instantly emitted from the share field and went undetected by FT-IR. On the other hand, under static conditions, liquid-like water produced on the surface remained at the site of generation and increased in amount with time. Subsequently,<\$%&?>to<\$%&?>clarify<\$%&?>the<\$%&?>relationship<\$%&?>between<\$%&?>sliding,<\$%&?>corrosion ,<\$%&?>and<\$%&?>the<\$%&?>generation<\$%&?>of<\$%&?>liquid-like<\$%&?>water,<\$%&?>we<\$%&?>attempted<\$% &?>to<\$%&?>investigate<\$%&?>the<\$%&?>water<\$%&?>behavior<\$%&?>in<\$%&?>the<\$%&?>rotating<\$%&?>state.<\$ %&?>Tests<\$%&?>were<\$%&?>conducted<\$%&?>at<\$%&?>10<\$%&?>rpm<\$%&?>of<\$%&?>disk<\$%&?>rotation<\$%& ?>from<\$%&?>the<\$%&?>test<\$%&?>start.<\$%&?>The<\$%&?>test<\$%&?>duration<\$%&?>was<\$%&?>8<\$%&?>h,<\$% &?>and<\$%&?>the<\$%&?>humidity<\$%&?>was<\$%&?>3.8<\$%&?>g/m3<\$%&?>(relative<\$%&?>humidity:<\$%&?>20%) .<\$%&?>Time<\$%&?>variations<\$%&?>in<\$%&?>the<\$%&?>IR<\$%&?>spectrum<\$%&?>are<\$%&?>shown<\$%&?>in<\$ %&?>Figure<\$%&?>4(a).<\$%&?>During<\$%&?>the<\$%&?>test<\$%&?>period,<\$%&?>the<\$%&?>O-H<\$%&?>stretchin g<\$%&?>mode<\$%&?>corresponding<\$%&?>to<\$%&?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>not<\$%&?>observe d,<\$%&?>indicating<\$%&?>that<\$%&?>water<\$%&?>is<\$%&?>absorbed<\$%&?>into<\$%&?>the<\$%&?>ionic<\$%&?>liq uid<\$%&?>as<\$%&?>free<\$%&?>water.<\$%&?>Corrosion<\$%&?>was<\$%&?>observed<\$%&?>from<\$%&?>the<\$%&?> surface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>(Figure<\$%&?>4(b)),<\$%&?>even<\$%&?>though<\$%& ?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>not<\$%&?>observed.<\$%&?>The<\$%&?>reason<\$%&?>for<\$%&?>this<\$

To confirm this consideration, we performed the test in the following sequence: the rotating state was maintained from the start of the test until 0.5 h had elapsed; subsequently, the disk was stopped and kept in a static state for 8 h. The test duration was set to 8 h for comparison with the rotation test. The humidity was 4.0 g/m3 (relative humidity: 22%). Figure 5(a) shows the variation in the IR spectrum over time. The intensity of the O-H peak corresponding to liquid-like water increased immediately after stopping the disk rotation. The corrosion proceeded in the rotation and static test (Figure 5(b)) than in the rotation test (Figure 4(b)). This result agrees with the results observed under static conditions; that is, the increase in the amount of liquid-like water relates to the corrosion. %&?>result<\$%&?>is<\$%&?>because<\$%&?>scratch<\$%&?>scars<\$%&?>induced<\$%&?>by<\$%&?>sliding<\$%&?>wer e<\$%&?>created<\$%&?>at<\$%&?>the<\$%&?>pin<\$%&?>surface.<\$%&?>The<\$%&?>scars<\$%&?>gave<\$%&?>rise<\$% &?>to<\$%&?>a<\$%&?>topical<\$%&?>potential<\$%&?>difference,<\$%&?>consequently<\$%&?>resulting<\$%&?>in<\$% &?>a<\$%&?>galvanic<\$%&?>corrosion<\$%&?>environment.<\$%&?>The<\$%&?>absence<\$%&?>of<\$%&?>liquid-like<\$ %&?>water<\$%&?>under<\$%&?>rotating<\$%&?>conditions<\$%&?>was<\$%&?>rationalized<\$%&?>as<\$%&?>follows:< \$%&?>even<\$%&?>if<\$%&?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>produced<\$%&?>near<\$%&?>the<\$%&?>frict

hand,<\$%&?>under<\$%&?>static<\$%&?>conditions,<\$%&?>liquid-like<\$%&?>water<\$%&?>produced<\$%&?>on<\$%& ?>the<\$%&?>surface<\$%&?>remained<\$%&?>at<\$%&?>the<\$%&?>site<\$%&?>of<\$%&?>generation<\$%&?>and<\$%&?> increased<\$%&?>in<\$%&?>amount<\$%&?>with<\$%&?>time. Vibrational Spectroscopic Study on Lubrication and Corrosive Wear Mechanisms of Imidazolium Based Ionic Liquids http://dx.doi.org/10.5772/59132 549

ional<\$%&?>surface,<\$%&?>it<\$%&?>was<\$%&?>instantly<\$%&?>emitted<\$%&?>from<\$%&?>the<\$%&?>share<\$%&? >field<\$%&?>and<\$%&?>went<\$%&?>undetected<\$%&?>by<\$%&?>FT-IR.<\$%&?>On<\$%&?>the<\$%&?>other<\$%&?>

erved<\$%&?>under<\$%&?>static<\$%&?>conditions;<\$%&?>that<\$%&?>is,<\$%&?>the<\$%&?>increase<\$%&?>in<\$%&? Figure 4. Rotation<\$%&?>condition<\$%&?>test<\$%&?>for<\$%&?>8<\$%&?>hours<\$%&?>at<\$%&?>3.8<\$%&?>g/m3<\$%&?>(a)<\$%&?>Tim e<\$%&?>dependent<\$%&?>change<\$%&?>of<\$%&?>FT-IR<\$%&?>spectra<\$%&?>of<\$%&?>[BMIM]OTf,<\$%&?>(b)<\$%&?>pin<\$%&? >surface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>[9] **Figure 4.** Rotation condition test for 8 hours at 3.8 g/m3 (a) Time dependent change of FT-IR spectra of [BMIM]OTf, (b) pin surface image after the test [9]

>the<\$%&?>amount<\$%&?>of<\$%&?>liquid-like<\$%&?>water<\$%&?>relates<\$%&?>to<\$%&?>the<\$%&?>corrosion.

?>set<\$%&?>to<\$%&?>8<\$%&?>h<\$%&?>for<\$%&?>comparison<\$%&?>with<\$%&?>the<\$%&?>rotation<\$%&?>test.<\$

In summary, there are two states of water in [BMIM] OTf: free water and liquid-like water. In addition, it is indicated that liquid-like water significantly affects the corrosion of ferrous materials. In<\$%&?>summary,<\$%&?>there<\$%&?>are<\$%&?>two<\$%&?>states<\$%&?>of<\$%&?>water<\$%&?>in<\$%&?>[BMIM ]<\$%&?>OTf:<\$%&?>free<\$%&?>water<\$%&?>and<\$%&?>liquid-like<\$%&?>water.<\$%&?>In<\$%&?>addition,<\$%&?> it<\$%&?>is<\$%&?>indicated<\$%&?>that<\$%&?>liquid-like<\$%&?>water<\$%&?>significantly<\$%&?>affects<\$%&?>the <\$%&?>corrosion<\$%&?>of<\$%&?>ferrous<\$%&?>materials. To<\$%&?>confirm<\$%&?>this<\$%&?>consideration,<\$%&?>we<\$%&?>performed<\$%&?>the<\$%&?>test<\$%&?>in<\$% &?>the<\$%&?>following<\$%&?>sequence:<\$%&?>the<\$%&?>rotating<\$%&?>state<\$%&?>was<\$%&?>maintained<\$% &?>from<\$%&?>the<\$%&?>start<\$%&?>of<\$%&?>the<\$%&?>test<\$%&?>until<\$%&?>0.5<\$%&?>h<\$%&?>had<\$%&?>e lapsed;<\$%&?>subsequently,<\$%&?>the<\$%&?>disk<\$%&?>was<\$%&?>stopped<\$%&?>and<\$%&?>kept<\$%&?>in<\$% &?>a<\$%&?>static<\$%&?>state<\$%&?>for<\$%&?>8<\$%&?>h.<\$%&?>The<\$%&?>test<\$%&?>duration<\$%&?>was<\$%&

the humidity was 3.8 g/m3

surface image after the test [9]

absorbance (a.u.)

(b) (b)

548 Ionic Liquids - Current State of the Art

(relative humidity: 20%). Time variations in the IR spectrum are

(relative humidity: 22%). Figure 5(a) shows

60

40

Time (hr)

20

0

(a) Humidity 6.0 g/m3

shown in Figure 4(a). During the test period, the O-H stretching mode corresponding to liquidlike water was not observed, indicating that water is absorbed into the ionic liquid as free water. Corrosion was observed from the surface image after the test (Figure 4(b)), even though liquid-like water was not observed. The reason for this result is because scratch scars induced by sliding were created at the pin surface. The scars gave rise to a topical potential difference, consequently resulting in a galvanic corrosion environment. The absence of liquid-like water under rotating conditions was rationalized as follows: even if liquid-like water was produced near the frictional surface, it was instantly emitted from the share field and went undetected by FT-IR. On the other hand, under static conditions, liquid-like water produced on the surface

**Figure 3.** Static condition test for 5 hours at 6.0 g/m3 (a) Time dependent change of FT-IR spectra of [BMIM]OTf,(b) pin

2800 3000 3200 3400 3600 3800 Wavenumber (cm-1

)

Figure 3. .<\$%&?>Static<\$%&?>condition<\$%&?>test<\$%&?>for<\$%&?>5<\$%&?>hours<\$%&?>at<\$%&?>6.0<\$%&?>g/m3<\$%&?>(a)<\$%& ?>Time<\$%&?>dependent<\$%&?>change<\$%&?>of<\$%&?>FT-IR<\$%&?>spectra<\$%&?>of<\$%&?>[BMIM]OTf,(b)<\$%&?>pin<\$%&?>s

Subsequently,<\$%&?>to<\$%&?>clarify<\$%&?>the<\$%&?>relationship<\$%&?>between<\$%&?>sliding,<\$%&?>corrosion ,<\$%&?>and<\$%&?>the<\$%&?>generation<\$%&?>of<\$%&?>liquid-like<\$%&?>water,<\$%&?>we<\$%&?>attempted<\$% &?>to<\$%&?>investigate<\$%&?>the<\$%&?>water<\$%&?>behavior<\$%&?>in<\$%&?>the<\$%&?>rotating<\$%&?>state.<\$ %&?>Tests<\$%&?>were<\$%&?>conducted<\$%&?>at<\$%&?>10<\$%&?>rpm<\$%&?>of<\$%&?>disk<\$%&?>rotation<\$%& ?>from<\$%&?>the<\$%&?>test<\$%&?>start.<\$%&?>The<\$%&?>test<\$%&?>duration<\$%&?>was<\$%&?>8<\$%&?>h,<\$% &?>and<\$%&?>the<\$%&?>humidity<\$%&?>was<\$%&?>3.8<\$%&?>g/m3<\$%&?>(relative<\$%&?>humidity:<\$%&?>20%) .<\$%&?>Time<\$%&?>variations<\$%&?>in<\$%&?>the<\$%&?>IR<\$%&?>spectrum<\$%&?>are<\$%&?>shown<\$%&?>in<\$ %&?>Figure<\$%&?>4(a).<\$%&?>During<\$%&?>the<\$%&?>test<\$%&?>period,<\$%&?>the<\$%&?>O-H<\$%&?>stretchin g<\$%&?>mode<\$%&?>corresponding<\$%&?>to<\$%&?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>not<\$%&?>observe d,<\$%&?>indicating<\$%&?>that<\$%&?>water<\$%&?>is<\$%&?>absorbed<\$%&?>into<\$%&?>the<\$%&?>ionic<\$%&?>liq uid<\$%&?>as<\$%&?>free<\$%&?>water.<\$%&?>Corrosion<\$%&?>was<\$%&?>observed<\$%&?>from<\$%&?>the<\$%&?> surface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>(Figure<\$%&?>4(b)),<\$%&?>even<\$%&?>though<\$%& ?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>not<\$%&?>observed.<\$%&?>The<\$%&?>reason<\$%&?>for<\$%&?>this<\$ %&?>result<\$%&?>is<\$%&?>because<\$%&?>scratch<\$%&?>scars<\$%&?>induced<\$%&?>by<\$%&?>sliding<\$%&?>wer e<\$%&?>created<\$%&?>at<\$%&?>the<\$%&?>pin<\$%&?>surface.<\$%&?>The<\$%&?>scars<\$%&?>gave<\$%&?>rise<\$% &?>to<\$%&?>a<\$%&?>topical<\$%&?>potential<\$%&?>difference,<\$%&?>consequently<\$%&?>resulting<\$%&?>in<\$% &?>a<\$%&?>galvanic<\$%&?>corrosion<\$%&?>environment.<\$%&?>The<\$%&?>absence<\$%&?>of<\$%&?>liquid-like<\$ %&?>water<\$%&?>under<\$%&?>rotating<\$%&?>conditions<\$%&?>was<\$%&?>rationalized<\$%&?>as<\$%&?>follows:< \$%&?>even<\$%&?>if<\$%&?>liquid-like<\$%&?>water<\$%&?>was<\$%&?>produced<\$%&?>near<\$%&?>the<\$%&?>frict

To confirm this consideration, we performed the test in the following sequence: the rotating state was maintained from the start of the test until 0.5 h had elapsed; subsequently, the disk was stopped and kept in a static state for 8 h. The test duration was set to 8 h for comparison

the variation in the IR spectrum over time. The intensity of the O-H peak corresponding to liquid-like water increased immediately after stopping the disk rotation. The corrosion proceeded in the rotation and static test (Figure 5(b)) than in the rotation test (Figure 4(b)). This result agrees with the results observed under static conditions; that is, the increase in the

remained at the site of generation and increased in amount with time.

urface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test<\$%&?>[9]

with the rotation test. The humidity was 4.0 g/m3

amount of liquid-like water relates to the corrosion.

Figure 5. Rotation<\$%&?>and<\$%&?>static<\$%&?>condition<\$%&?>test<\$%&?>for<\$%&?>8<\$%&?>hours<\$%&?>at<\$%&?>4.0<\$%&? >g/m3<\$%&?>(a)<\$%&?>Time<\$%&?>dependent<\$%&?>change<\$%&?>of<\$%&?>FT-IR<\$%&?>spectra<\$%&?>of<\$%&?>[BMIM]OTf,<\$% **Figure 5.** Rotation and static condition test for 8 hours at 4.0 g/m3 (a) Time dependent change of FT-IR spectra of [BMIM]OTf, (b) pin surface image after the test

**3. Effect<\$%&?>of<\$%&?>the<\$%&?>solid-liquid<\$%&?>interface<\$%&?>of<\$%&?>ionic<\$%& ?>liquid<\$%&?>on<\$%&?>frictional<\$%&?>property<\$%&?>–<\$%&?>analysis<\$%&?>by<\$%&?**

For<\$%&?>the<\$%&?>effective<\$%&?>design<\$%&?>of<\$%&?>ionic<\$%&?>liquids<\$%&?>to<\$%&?>be<\$%&?>used<\$ %&?>as<\$%&?>lubricants<\$%&?>in<\$%&?>practical<\$%&?>applications,<\$%&?>it<\$%&?>is<\$%&?>important<\$%&?>t o<\$%&?>clarify<\$%&?>the<\$%&?>relationship<\$%&?>between<\$%&?>molecular<\$%&?>structure<\$%&?>and<\$%&?>f rictional<\$%&?>properties.<\$%&?>Because<\$%&?>an<\$%&?>ionic<\$%&?>liquid<\$%&?>forms<\$%&?>a<\$%&?>charact eristic<\$%&?>interfacial<\$%&?>structure<\$%&?>that<\$%&?>differs<\$%&?>from<\$%&?>the<\$%&?>liquid<\$%&?>bulk,

&?>(b)<\$%&?>pin<\$%&?>surface<\$%&?>image<\$%&?>after<\$%&?>the<\$%&?>test

**>SFG<\$%&?>spectroscopy<\$%&?>[12]**

**3.1. Experimental**

### **3. Effect of the solid-liquid interface of ionic liquid on frictional property – Analysis by SFG spectroscopy [12]**

#### **3.1. Experimental**

For the effective design of ionic liquids to be used as lubricants in practical applications, it is important to clarify the relationship between molecular structure and frictional proper‐ ties. Because an ionic liquid forms a characteristic interfacial structure that differs from the liquid bulk, we investigated the relationship between the frictional properties and the layer structure of ionic liquid formed at the interface. As mentioned in section 2, ionic liquids are understood to undergo complex chemical reactions with the surface of ferrous materi‐ als. Therefore, to minimize the influence of such reactions, we used a self-assembly monolayer (SAM) formed on a gold substrate as a model surface. In this study, we analyze the interfacial structure of an ionic liquid at SAM surfaces using SFG spectroscopy and discuss the effect of the interfacial structure of imidazolium-based ionic liquids on the frictional properties. Three 1-butyl-3-methylimidazolium [BMIM]-based ionic liquids were used: [BMIM]OTf, which is miscible with water; hexafluorophosphate ([BMIM]PF6), which is water-insoluble; and tricyanomethide ([BMIM]TCC), which is water-insoluble and halogen-free. Mercaptohexadecanoic acid (MHDA), which forms a hydrophilic surface, was selected. The basics of SFG are as follows. Two pulsed laser beams, one of mode-rocked visible frequency (*ω*vis) and the other of variable-wavelength IR frequency (*ω*IR) are overlapped at a surface, and the nonlinear optical effect of SFG results in the emission of light at *ω*SFG=*ω*vis+*ω*IR; this SFG light is detected. The intensity of the SFG light (*I*SFG) is proportional to |*χ*(2)|2 , where *χ*(2) is the second-order nonlinear susceptibility. Because *χ*(2) is zero in centrosymmetric environments, SFG spectroscopy can be used to selectively probe the surface and interface [13, 14]. SFG measurements were conducted over the 2800–3200 cm-1 wavenumber range, which includes the C-H stretching mode peaks and polarization of ppp (SFG, visible, infrared). In addition, the molecular orientation can be determined from the SFG intensity. In this study, the orientation angle of the imidazolium ring was analyzed. The obtained SFG spectra were fitted using the following function [15,16]:

$$I^{SFG} \left( \alpha\_2 \right) \propto \left| \mathcal{Z}\_{NR}^{(2)} + \sum\_{q} \frac{A\_q}{\alpha\_2 - \alpha\_q + i\Gamma\_q} \right|^2 \tag{1}$$

χ(2)NR represents the nonresonant term and ω2 represents the frequency of the IR light. Aq, ωq, and Γ<sup>q</sup> correspond to the amplitude, vibration frequency, and damping factor of the qth vibrational mode, respectively. We calculated the peak intensity from the relationship between A and Γ, which is obtained from the fitting result.

Vibrational Spectroscopic Study on Lubrication and Corrosive Wear Mechanisms of Imidazolium Based Ionic Liquids http://dx.doi.org/10.5772/59132 551

**3. Effect of the solid-liquid interface of ionic liquid on frictional property**

For the effective design of ionic liquids to be used as lubricants in practical applications, it is important to clarify the relationship between molecular structure and frictional proper‐ ties. Because an ionic liquid forms a characteristic interfacial structure that differs from the liquid bulk, we investigated the relationship between the frictional properties and the layer structure of ionic liquid formed at the interface. As mentioned in section 2, ionic liquids are understood to undergo complex chemical reactions with the surface of ferrous materi‐ als. Therefore, to minimize the influence of such reactions, we used a self-assembly monolayer (SAM) formed on a gold substrate as a model surface. In this study, we analyze the interfacial structure of an ionic liquid at SAM surfaces using SFG spectroscopy and discuss the effect of the interfacial structure of imidazolium-based ionic liquids on the frictional properties. Three 1-butyl-3-methylimidazolium [BMIM]-based ionic liquids were used: [BMIM]OTf, which is miscible with water; hexafluorophosphate ([BMIM]PF6), which is water-insoluble; and tricyanomethide ([BMIM]TCC), which is water-insoluble and halogen-free. Mercaptohexadecanoic acid (MHDA), which forms a hydrophilic surface, was selected. The basics of SFG are as follows. Two pulsed laser beams, one of mode-rocked visible frequency (*ω*vis) and the other of variable-wavelength IR frequency (*ω*IR) are overlapped at a surface, and the nonlinear optical effect of SFG results in the emission of light at *ω*SFG=*ω*vis+*ω*IR; this SFG light is detected. The intensity of the SFG light (*I*SFG) is

, where *χ*(2) is the second-order nonlinear susceptibility. Because *χ*(2)

2

 q

i

is zero in centrosymmetric environments, SFG spectroscopy can be used to selectively probe the surface and interface [13, 14]. SFG measurements were conducted over the 2800–3200 cm-1 wavenumber range, which includes the C-H stretching mode peaks and polarization of ppp (SFG, visible, infrared). In addition, the molecular orientation can be determined from the SFG intensity. In this study, the orientation angle of the imidazolium ring was analyzed. The obtained SFG spectra were fitted using the following function [15,16]:

2

w w

χ(2)NR represents the nonresonant term and ω2 represents the frequency of the IR light. Aq, ωq, and Γ<sup>q</sup> correspond to the amplitude, vibration frequency, and damping factor of the qth vibrational mode, respectively. We calculated the peak intensity from the relationship

q q

A

q

( )

w

between A and Γ, which is obtained from the fitting result.

SFG

I

2

(2)

µ +

NR

 c

**– Analysis by SFG spectroscopy [12]**

**3.1. Experimental**

550 Ionic Liquids - Current State of the Art

proportional to |*χ*(2)|2

$$I\_{\nu} = \left(\frac{\mathcal{A}\_{\nu}}{\Gamma\_{\nu}}\right)^{2} \tag{2}$$

The molecular orientation angle of the imidazolium ring was analyzed by the relation between the theoretical value and the experimental result of the peak intensity ratio of *ν*SSHC(4)-C(5)H to *ν*ASHC(4)-C(5)H. We assumed the stretching vibration of methylene but omitted the detailed molecular orientation analysis [17, 18]. Figure 6 shows the definition of the orientation angle (*θ*, *φ*, *χ*) of the imidazolium ring. A tilt angle *θ* of 0° is defined as the surface normal and that of 90° as parallel to the surface plane. A twist angle *φ* of 0° is defined as parallel to the surface and that of 90° as perpendicular to the surface. The azimuthal angle *χ* is within the plane of the surface. In this calculation, the average of the Euler angles can be calculated for the rotationally isotropic system in the interface plane, i.e., with no azimuthal angle *χ* dependence. Baldelli et al. noted that the twist angle *φ* of an imidazolium ring ranges from 0° to 30° because of molecular steric hindrance [17]. Therefore, we calculated the value of *φ* in this range.

In addition, we performed friction tests to investigate the effect of the interfacial structure of the ionic liquid at the MHDA surface on the frictional properties using a pin-on-plate recip‐ rocating friction tester. We used MHDA, which forms a hydrophilic surface on a gold substrate, as the plate specimen and borosilicate glass, with a tip diameter of 3 mm, as the pin. We conducted a sliding test at a reciprocating frequency of 0.1 Hz, amplitude of 10 mm, sliding speed of 1 mm/s, and load of 10 mN. The test duration was 180 min, and the friction test was performed four times for each ionic liquid.

**Figure 6.** Definition of imidazolium orientation angle in the laboratory coordination

#### **3.2. Results and discussion**

Figure 7 shows the SFG spectrum of each ionic liquid spin-coated on the MHDA surface, in the range of 3200–3050 cm-1. Three dip peaks were observed, which were attributed to the C-H stretching mode derived from the imidazolium ring: ~3127 cm-1 (*ν*C(2)H), ~3153 cm-1 (*ν*ASHC(4)-C(5)H), and ~3174 cm-1 (*ν*SSHC(4)-C(5)H) [18,19].

TCC, (b) OTf and (c)PF6 **Figure 7.** SFG spectrum in the range of 3200 – 3050cm-1 which includes C-H stretching mode peaks derived from cation of (a) TCC, (b) OTf and (c)PF6

Figure 8 shows the relationship between the SFG intensity ratio and the molecular orientation angle of the imidazolium ring, which is theoretically calculated. In addition, the figure includes the intensity ratios obtained from the fitting result of the SFG spectra in Figure 7. From the result of the molecular orientation analysis of the imidazolium ring, the imidazolium tilt angle *θ* is determined to be 30–33° for [BMIM]TCC, 40–45° for [BMIM]OTf, and 61–65° for [BMIM]PF6. This difference between the tilt angles for the three ionic liquids could be attributed to the respective anion sizes. The anion radii follow the order PF6 (1.57 Å) <

Figure 7. SFG spectrum in the range of 3200 – 3050cm-1 which includes C-H stretching mode peaks derived from cation of (a)

―9―

Figure 8 shows the relationship between the SFG intensity ratio and the molecular orientation angle of the imidazolium ring, which is theoretically calculated. In addition, the figure includes the intensity ratios obtained from the fitting result of the SFG spectra in Figure 7. From the result of the molecular orientation analysis of the imidazolium ring, the imidazolium tilt angle *θ* is determined to be 30–33° for [BMIM]TCC, 40–45° for [BMIM]OTf, and 61–65° for [BMIM]PF6. This difference between the tilt angles for the three ionic liquids could be attributed to the respective anion sizes. The anion radii follow the order PF6 (1.57 Å) < OTf (1.94 Å) < TCC (2.57 Å); that is, PF6 had the smallest size. Thus, there is a clear relationship between the anion size and the tilt angle of the imidazolium ring; that is, a smaller anion results in a larger tilt angle.

**Figure 8.** The relation between SFG intensity ratio of *ν*SSHC(4)-C(5)H to *ν*ASHC(4)-C(5)H and molecular orientation an‐ gle of imidazolium ring.

Figure 9 shows the relationship between the tilt angle of the imidazolium ring and the mean value of the friction coefficient. [BMIM]PF6 exhibited the lowest friction coefficient, followed by [BMIM]OTf and [BMIM]TCC. In addition, the results indicated a clear trend: the larger the imidazolium ring tilt angle, the smaller was the corresponding friction coefficient.

We now discuss how the tilt angle of the imidazolium ring affects the frictional properties under a shear field. We propose two possible explanations for the tilt-angle dependence on the frictional properties: the film formation ability and the energy loss by molecular motion.

**•** Film formation ability

**3.2. Results and discussion**

552 Ionic Liquids - Current State of the Art

(*ν*ASHC(4)-C(5)H), and ~3174 cm-1 (*ν*SSHC(4)-C(5)H) [18,19].

H3C <sup>6</sup> N 3

0.14

0.12

SFG Intensity

0.10

0.08

1.4

1.3

SFG Intensity

1.2

1.1

0.45

0.40

SFG Intensity

TCC, (b) OTf and (c)PF6

of (a) TCC, (b) OTf and (c)PF6

0.35

Figure 7 shows the SFG spectrum of each ionic liquid spin-coated on the MHDA surface, in the range of 3200–3050 cm-1. Three dip peaks were observed, which were attributed to the C-H stretching mode derived from the imidazolium ring: ~3127 cm-1 (*ν*C(2)H), ~3153 cm-1

> C 5

> > C2

C <sup>7</sup> C 8

C

<sup>9</sup> CH3 <sup>10</sup>

C 4

(SS) (AS)

H-C4-C5-H -H

C <sup>2</sup> N+ 1

3200 3150 3100 3050 Wavenumber (cm-1

3200 3150 3100 3050 Wavenumber (cm-1

3200 3150 3100 3050 Wavenumber (cm-1

)

)

)

(a)TCC

(b)OTf

(c)PF6

―9―

Figure 8 shows the relationship between the SFG intensity ratio and the molecular orientation angle of the imidazolium ring, which is theoretically calculated. In addition, the figure includes the intensity ratios obtained from the fitting result of the SFG spectra in Figure 7. From the result of the molecular orientation analysis of the imidazolium ring, the imidazolium tilt angle *θ* is determined to be 30–33° for [BMIM]TCC, 40–45° for [BMIM]OTf, and 61–65° for [BMIM]PF6. This difference between the tilt angles for the three ionic liquids could be attributed to the respective anion sizes. The anion radii follow the order PF6 (1.57 Å) <

Figure 7. SFG spectrum in the range of 3200 – 3050cm-1 which includes C-H stretching mode peaks derived from cation of (a)

**Figure 7.** SFG spectrum in the range of 3200 – 3050cm-1 which includes C-H stretching mode peaks derived from cation

A small anion forms a dense film because in this case, the distance between the anion and the cation is short. This dense film is capable of supporting a load and preventing serious break‐ down, consequently leading to friction reduction.

Figure 9. The relation between tilt angle of imidazolium and friction coefficient **Figure 9.** The relation between tilt angle of imidazolium and friction coefficient

**•** Energy loss by molecular motion

The molecular motion hypothesis is based on the supposition that the entire surface layer of the ionic liquid has sufficient ability to support a load and prevent serious breakdown. The diagonal length of the imidazolium ring is approximately 1.12 Å, which is comparable to the radius of the PF6 anion (1.57 Å); consequently, a smoother and better-defined shear plane is formed [20]. This smooth surface limits energy loss by the rotation of the imidazolium ring, and the shear-induced increase in the lattice spacing of the surface layer of the ionic liquid. As a result, friction would be reduced. On the other hand, the difference in size between the imidazolium ring and the OTf or TCC anion might make the surface rough. Under a shear field, energy is needed for the rotation of the imidazolium ring and extension of the lattice spacing of the surface layer of the ionic liquid, so that the rough surface is smoothened. We now discuss how the tilt angle of the imidazolium ring affects the frictional properties under a shear field. We propose two possible explanations for the tilt-angle dependence on the frictional properties: the film formation ability and the energy loss by molecular motion. Film formation ability A small anion forms a dense film because in this case, the distance between the anion and the cation is short. This dense film is capable of supporting a load and preventing serious breakdown, consequently leading to friction reduction. Energy loss by molecular motion The molecular motion hypothesis is based on the supposition that the entire surface layer of the ionic liquid has sufficient ability

to support a load and prevent serious breakdown. The diagonal length of the imidazolium ring is approximately 1.12 Å, which is comparable to the radius of the PF6 anion (1.57 Å); consequently, a smoother and better-defined shear plane is formed [20]. This

#### **4. Conclusion** smooth surface limits energy loss by the rotation of the imidazolium ring, and the shear-induced increase in the lattice spacing of the surface layer of the ionic liquid. As a result, friction would be reduced. On the other hand, the difference in size between the

We investigated the mechanisms of corrosive wear and lubrication of ionic liquids from the viewpoint of molecular behavior. FT-IR results indicated the presence of two types of water phases within [BMIM]OTf, viz., free water and liquid-like water; the liquid-like water has a more pronounced effect on corrosion. In addition, comparison of the results of molecular orientation analysis by SFG spectroscopy and the results of friction tests revealed that the tilt angle of the imidazolium ring affects the frictional properties of the ionic liquid. the imidazolium ring and extension of the lattice spacing of the surface layer of the ionic liquid, so that the rough surface is smoothened. 4. Conclusion We investigated the mechanisms of corrosive wear and lubrication of ionic liquids from the viewpoint of molecular behavior.

imidazolium ring and the OTf or TCC anion might make the surface rough. Under a shear field, energy is needed for the rotation of

―11―

Thus, a combination of friction tests with FT-IR or SFG spectroscopy enables us to evaluate tribochemical reactions or the relationship between the interfacial molecular arrangement and the frictional properties. These methods serve to advance the understanding of interfacial phenomena in the field of tribology.

### **Author details**

Seiya Watanabe1 , Miki Nakano2 , Koji Miyake2 , Chiharu Tadokoro1 and Shinya Sasaki1\*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan

2 National Institute of Advanced Industrial Science and Technology, Namiki, Tsukuba, Ibaraki, Japan

#### **References**

**•** Energy loss by molecular motion

0.28

554 Ionic Liquids - Current State of the Art

0.26

0.24

0.22

0.20

Friction Coefficient

0.18

0.16

0.14

0.12

**Figure 9.** The relation between tilt angle of imidazolium and friction coefficient

**4. Conclusion**

smoothened.

4. Conclusion

molecular motion.

Film formation ability

Energy loss by molecular motion

The molecular motion hypothesis is based on the supposition that the entire surface layer of the ionic liquid has sufficient ability to support a load and prevent serious breakdown. The diagonal length of the imidazolium ring is approximately 1.12 Å, which is comparable to the radius of the PF6 anion (1.57 Å); consequently, a smoother and better-defined shear plane is formed [20]. This smooth surface limits energy loss by the rotation of the imidazolium ring, and the shear-induced increase in the lattice spacing of the surface layer of the ionic liquid. As a result, friction would be reduced. On the other hand, the difference in size between the imidazolium ring and the OTf or TCC anion might make the surface rough. Under a shear field, energy is needed for the rotation of the imidazolium ring and extension of the lattice spacing of the surface layer of the ionic liquid, so that the rough surface is smoothened.

We now discuss how the tilt angle of the imidazolium ring affects the frictional properties under a shear field. We propose two possible explanations for the tilt-angle dependence on the frictional properties: the film formation ability and the energy loss by

A small anion forms a dense film because in this case, the distance between the anion and the cation is short. This dense film is

The molecular motion hypothesis is based on the supposition that the entire surface layer of the ionic liquid has sufficient ability to support a load and prevent serious breakdown. The diagonal length of the imidazolium ring is approximately 1.12 Å, which is comparable to the radius of the PF6 anion (1.57 Å); consequently, a smoother and better-defined shear plane is formed [20]. This smooth surface limits energy loss by the rotation of the imidazolium ring, and the shear-induced increase in the lattice spacing of the surface layer of the ionic liquid. As a result, friction would be reduced. On the other hand, the difference in size between the imidazolium ring and the OTf or TCC anion might make the surface rough. Under a shear field, energy is needed for the rotation of the imidazolium ring and extension of the lattice spacing of the surface layer of the ionic liquid, so that the rough surface is

capable of supporting a load and preventing serious breakdown, consequently leading to friction reduction.

TCC OTf PF6

TCC OTf PF6

Figure 9. The relation between tilt angle of imidazolium and friction coefficient

Friction Coefficient

Tilt Angle

80

70

60

50

Tilt Angle (deg)

40

30

20

We investigated the mechanisms of corrosive wear and lubrication of ionic liquids from the viewpoint of molecular behavior. FT-IR results indicated the presence of two types of water phases within [BMIM]OTf, viz., free water and liquid-like water; the liquid-like water has a more pronounced effect on corrosion. In addition, comparison of the results of molecular orientation analysis by SFG spectroscopy and the results of friction tests revealed that the tilt

―11―

We investigated the mechanisms of corrosive wear and lubrication of ionic liquids from the viewpoint of molecular behavior.

angle of the imidazolium ring affects the frictional properties of the ionic liquid.


Research Trends and Challenges in Smart Grids

Until the last decade, it was the least smart domain and the source of most of power outages and disturbances, due to the lack of monitoring and control capabilities. Smart grid transition is starting right from this domain, with a large deployment of smart systems, coupled with two-way communication links.

• Energy management: Monitoring and controlling energy efficiency and demand

• Aggregation: Aggregating different customers and producers and efficiently managing the system as a whole, enabling new paradigms such as virtual

Introductory Chapter: Open Problems and Enabling Methodologies for Smart Grids

Customer domain is what defines the goal of a smart grid. This domain can be divided into three subdomains, each of which collects different customers with similar behaviors and energy needs: industrial, residential, and commercial. It is

With the introduction of distributed energy sources, the customer is evolving to a prosumer, i.e., it both produces and consumes energy, and it has an active role in

Most of energy efficiency policies are addressed to this domain, and automation

Electrical vehicles are expecting to take an important place in vehicle market, due to the increasing focus on sustainability, energy supply security, and climate change. They have the potential to serve electric grid as dynamical energy storages. Since they are parked most of the time, they can remain connected to the grid [10]. Vehicle to grid is a concept that enables electrical vehicles to interact with power systems, in order to provide a series of functions to support the grid, such as peak power shaving, spinning reserve, voltage, and frequency regulation. Such opportunities are provided by electric vehicles through charging and discharging of their

Their integration into power grids has to be carefully evaluated in order to avoid

One of the most promising strategies for the integration of vehicle-to-grid tech-

microgrid concepts, in such a way that energy flows are optimally controlled, taking into account power system's constraints, thus reducing eventual stress on the grid.

A novel concept, potentially introducing further flexibility into power systems,

An energy hub is a unit where multiple energy carriers, such as natural gas and electric energy, can be converted, conditioned, and stored. A typical example of converter is the CHP generator that produces both electric and thermal energy,

The main advantages of energy hubs are the increased reliability of supply and higher flexibility. Such concept would add another choice to the participants to demand response, maintaining the same absorbed power but switching the primary energy source from electrical energy coming from the grid to another carrier, such as natural gas. In that case the customer would get the benefits of the demand response incentives without renouncing the part of the absorbed power.

nology is the aggregation of electrical vehicles to the virtual power plant or

Key and innovative concepts for the customers of the future are demand

response, described earlier, vehicle to grid (V2G) and energy hubs.

of customers

DOI: http://dx.doi.org/10.5772/intechopen.86496

power plants

2.7 Customer domain

power systems.

2.7.1 Vehicle to grid

battery packs.

2.7.2 Energy hubs

7

is that of energy hubs.

taking natural gas as input [11].

electrically connected to the distribution domain.

is playing a big role in reshaping it.

technical problems in distribution systems.

An evolving concept related to distributed generation, smart monitoring, and controls are microgrids.