**1. Introduction**

4-Nitrobenzofurazan (NBD) is neutral 10π electron-deficient heteroaromatic substrates. Organic materials containing the NBD moiety have been tested in

potential biomedical and bio-analytical applications [1–7]. They have been also used as an effective electron-withdrawing building block for organic solar cell materials [8], and have been discovered to be nonlinear optical (NLO) materials [9]. In addition, the strong electron withdrawing properties of nitrobenzofurazan (NBD) derivatives make it an exceptional electrophilic product of the nucleophilic aromatic substitution (SNAr).

In addition, the activated chlorine atom in 4-chloro-7-nitrobenzofurazan (NBD chloride, namely NBD-Cl) can undergo electrophilic aromatic substitution by phenoxide, primary or secondary cyclic amines [10–13] and some of 4,7 di-substituted benzofurazan compounds to generate weakly or non-fluorescents products [14–18].

A previous kinetic study of amino-substituted NBD showed that methoxy and aryloxy substituent's are better leaving groups than chloro and that a red-colored Meisenheimer complex immediate was formed during the reactions [19].

On the other hand, the frontier molecular orbital descriptors including HOMO and LUMO energy levels play major roles in governing many chemical reactions as function of reactivity and stability of related molecules [20, 21]. Alternatively, contacts from intra-molecular interactions have been identified as an important driving force on the stabilization of various planar molecular structures [22, 23]. However, these interactions lead to intra-molecular charge transfer of formed compounds and thus provides a non-radiative decay from the excited state [24–26].

Recently, we reported a kinetic study for SNAr reactions of NBD with secondary amines [27–30]. The present chapter is focused on the elucidation of the combined experimental–theoretical investigation relationships between the optical (UV–Vis, PL and time resolved photoluminescence (TR-PL), electrochemical (CV) properties and the chemical structures of 4.7-di-substituted benzofurazans (NBDs), based on the kinetic reactivity process of compounds. Parr's approach was employed to develop a relationship which rationalizes the kinetic data previously reported for the reactions of 4-X-7-nitrobenzofurazans with various nucleophiles [27–29].

Then, the substituent effects were particularly limited only to morpholine, piperidine and pyrrolidine groups. Thus, we seek to study the structure–property relationships for molecules containing 4-nitrobenzofurazan moiety for a better understanding of their optical behavior and their chemical reactivity. For this aim, theoretical calculations using quantum chemical calculations within density functional theory (DFT) and its extension TD-DFT in the 6-31 + g(d,p) basis set have been developed to facilitate the in-depth understanding of structure–property relationships.

The Molecular structures of the investigated compounds are illustrated in **Figures 1** and **2**.

To the best of our knowledge, no similar study has been published on electrochemical and photo-physical properties of the studied compounds. Cyclic Voltammetry (CV) is used to estimate the band gaps, electron affinities (i.e. the

**Figure 1.** *Chemical structures of the studied electrophile compounds.*

*Structure-Property Relationships in Benzofurazan Derivatives: A Combined Experimental… DOI: http://dx.doi.org/10.5772/intechopen.99246*

**Figure 2.**

*Reaction mechanism between NBD-Cl and three examples of nucleophiles (morpholine, piperidine and pyrrolidine) groups.*

energy of LUMO, εLUMO) and ionization potentials (i.e., the energy of HOMO, εHOMO) [31]. Besides, the computed results from DFT and TD-DFT calculations enable the access to the structure geometry, the Mullikan charge distribution and the dipole moment of the 4,7 di-substituted benzofurazan at the ground- (S0) and excited (S1)-states [32, 33].


**1.4 Risk factors**

Neonatal VTE is frecuently associated with presence of significant underlying risk factors. As in older children central venous lines (CVLs) are the single most important contributing factor. Excluding cases of renal vein thrombosis (RVT), CVLs-related thrombosis accounted for 89% and 94% of VTE in the Canadian and Dutch registries, respectively (Schmidt and Andrew, 1995; van Ommen et al., 2001). These events involve the large vessels most frequently used for catheterization including the umbilical vein. Neonatal VTE related to the use of the umbilical venous catheter (UVC) has been the subject of studies involving sequential imaging. Using venography, Roy et al.,1997 documented UVC-associated thrombosis in 14 of 48 neonates (29%). As in older children, many of these events were asymptomatic and the incidence of thrombosis was highly dependent on the imaging modality used (Chalmers, 2006).

Critical illness is a well-recognized risk factor for TE in all age groups. Inmobilization, rapid changes in intravascular volume and extensive intravascular instrumentation contribute to the enhanced risk of venous and arterial thrombosis in patients in intensive care units. (Veldman, 2008). Additional risk factors include, but are not limited to, asphyxia, maternal diabetes, poor cardiac output and dehydration. Neonates are born with a high hematocrit and tend to contract their intravascular volume within the first days of life, making them even more prone to thromboembolic events (Veldman, 2008).

In the neonatal population, sepsis is particularly devastating, as it causes 45% of late deaths in the neonatal intensive care unit (NICU). Neonates with sepsis develop an acquired prothrombotic state due to increased consumption of already limited supplies of coagulation Pathophysiology and Clinical Aspects of 38 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

On the pro-coagulant side, especially the vitamin K-dependent coagulation factors (II, VII, IX, and X) and the components of the contact system (FIX,FXII, prekallkreine and high molecular weight kininogen) show significantly reduced plasma activities in neonates compared to children and adults. However, the vitamin K-dependent inhibitors of coagulation, protein C and protein S, are also reduced, counterbalancing the reduced clotting potential of neonatal plasma. In fact, both antithrombin and protein C concentrantions are decreased to approximately 30% of adults values in term and even lower in preterm newborns. Neonatal platelets have been reported to be hypo-reactive; however, this deficiency seems to be balanced by increased von Willebrand factor activity,

The activity of the fibrinolityc system in the newborn is reduced compared to adults and older children due to both decreased plasma activity of plasminogen and increased plasma levels of plasminogen activator inhibitor (PAI). The latter fact may explain the high rate of thromboembolic event (TE) associated with intravascular devices in newborns. However, to date there is no evidence that the neonatal hemostatic system either protects from or promotes thrombus formation. Of course, additional risk factors, eg, critical illness or congenital thrombophilia, have to be considered separately from the immaturity of neonatal hemostasis (Veldman, 2008). Given the siginificant differences between the plasma factor concentrations in different age groups, a detailed knowledge on the development of hemostasis is critical for the intensivist in order to adapt pharmacological approaches and interpret results from laboratory tests in the neonate with TE (Ignjatovich et al,. 2006;

Neonatal VTE is frecuently associated with presence of significant underlying risk factors. As in older children central venous lines (CVLs) are the single most important contributing factor. Excluding cases of renal vein thrombosis (RVT), CVLs-related thrombosis accounted for 89% and 94% of VTE in the Canadian and Dutch registries, respectively (Schmidt and Andrew, 1995; van Ommen et al., 2001). These events involve the large vessels most frequently used for catheterization including the umbilical vein. Neonatal VTE related to the use of the umbilical venous catheter (UVC) has been the subject of studies involving sequential imaging. Using venography, Roy et al.,1997 documented UVC-associated thrombosis in 14 of 48 neonates (29%). As in older children, many of these events were asymptomatic and the incidence of thrombosis was highly dependent on the imaging

Critical illness is a well-recognized risk factor for TE in all age groups. Inmobilization, rapid changes in intravascular volume and extensive intravascular instrumentation contribute to the enhanced risk of venous and arterial thrombosis in patients in intensive care units. (Veldman, 2008). Additional risk factors include, but are not limited to, asphyxia, maternal diabetes, poor cardiac output and dehydration. Neonates are born with a high hematocrit and tend to contract their intravascular volume within the first days of life, making them

In the neonatal population, sepsis is particularly devastating, as it causes 45% of late deaths in the neonatal intensive care unit (NICU). Neonates with sepsis develop an acquired prothrombotic state due to increased consumption of already limited supplies of coagulation

resulting in overall normal platelet function (Veldman, 2008).

Ignjatovich et al,. 2007).

modality used (Chalmers, 2006).

even more prone to thromboembolic events (Veldman, 2008).

**1.4 Risk factors**

inhibitors. Furthermore, plasma activity of plasminogen activator inhibitor (PAI) is increased in sepsis and levels of protein C are reduced. The latter fact has been reported to correlate with poor outcomes in adults and neonates. Ongoing consumption of coagulation factors and platelets resulting in microcirculatory thrombosis likely contributes to sepsisinduced multi-organ failure and death. Macro-circulatory thrombotic events are rare in this setting but can occur, especially in babies who have arterial umbilical catheters (UACs) or UVCs in situ (Veldman, 2008).

Turebylu., 2007 reported that congenital thrombophilia not to be associated with UVC thrombosis. Revel-Vilk et al., 2003 reported that in neonates inherited prothrombotic coagulation proteins do not contribute significantly to the pathogenesis of venous TEs; they concluded that the most siginificant aetiological risk factors are the presence of a central venous line and other medical conditions.

Heller et al., 2000 reported an elevated odds ratio for the presence of congenital thrombophilia in neonates with renal, portal or hepatic venous thrombosis and recommended that neonates with TE should undergo an extensive screening, included resistance to activated protein C ( APC-R), protein C, protein S, antithrombin activity, activities of coagulation factors VIIIC and XII, lipoprotein-A, histidine-rich glycoprotein, heparin cofactor II, antiphospholipid antibodies, lupus anticoagulants, as well as fasting homocysteine concentrations. In addition, DNA-based assays (factor V G1691A mutation or factor V Leiden, factor II G20210A variant and MTHFR C677T genotype) should be considered. Whereas DNA-based mutation analysis can be performed at any time point, protein-based assays should not be carried out in the first 6-8 months after the event and oral anticoagulation is recommended to be discontinued at 14-30 days before plasma samples for thrombophilia diagnosis are drawn.

Deficiency of one of the important hemostasis control proteins, protein C, protein S or antithrombin, occurs less frequently, but results in a more potent prothrombotic state. Heterozygous deficiency of these proteins is difficult to diagnose in the newborn period, because the neonatal levels are much lower than the adult reference range. Homozygous deficiency of Protein C or S typically presents in the perinatal period with significant thrombosis resulting in purpura fulminans. Compoud heterozygosity of one of the natural anticoagulants in association with Factor V Leiden may cause a similar clinical picture (Beardsley, 2007).


**6.3 Hematopoietic stem cell transplantation (HSCT)**

Hematopoietic stem cell transplantation (HSCT) can normalize abnormal hemostatic derangement in β-thalassemia patients by increasing natural anticoagulant proteins and activating platelets in the circulation and reducing microparticles and Exposure of abnormal RBCs membrane to PS (results in reduction of normal dissemination of RBC membrane phospholipids) [2].


*6.3. A Di*ff*use Law Firm*

Finally, the new large law firm will be a diffuse law firm. Up until the 2008 financial crisis, the trend among large law firms was to expand their ranks often through mergers with and acquisition of smaller or medium size firms and/or by opening new offices in strategic locations.121 The logic behind these developments was that profitable legal projects could only be handled by large firms.122 The financial crisis, however, showed some of the flaws of this model in terms of profitability and capacity to manage giant firms. The increasing process of digitalization of legal services is furthering these developments and showing that the strategy of having a large, but centralized, law firm may not necessarily be the best one in terms of both maximizing profits and providing effective and client-oriented legal services. In my view, the centralized law firm that was developed in the last few decades should give way to what I label "the diffuse law firm". This will be smaller in size (perhaps reaching one hundred employees), while at the same time making a smart use of outsourcing strategies and technology to lower costs, increase effectiveness, and keep competitors at bay. In a way this is where legal practice meets the dynamics of the gig economy as interestingly put by the Managing Partner of a Danish large law firm:

A: Our organization needs to be extremely adaptable for continuing moving around the resources we have. And this also means that the lawyers we employ must be very, very adaptable themselves . . . which I think, to my surprise, they are, as I would not be so adaptable. But then again, I am 47, and many of our lawyers are 30 years old. It is a different game for them. But the reason I think the future will look different is the fact that . . . well, the Danish Bar Association has recently made a report on legal tech, in which they use the expression gig economy, which is defined as being: you get a job for a client and you need maybe five different competencies to solve the case, you maybe have two of them in house, so you need to obtain the three remaining. So, you go and get them, but it is not necessarily competences that you need in stock all the time, so you hire them for a particular job. For me this means that, in the future, I will not have 700 lawyers on the payroll all the time. I think we are looking to a future where we will be just as well off by hiring in the competencies that we need to solve particular tasks on a case by case basis.123 Of particular interest in this regard is the, now already "old", organizational technology known as Legal Process Outsourcing (LPO) and its newest incarnation Legal-Tech Process Outsourcing (LTPO). As expressed by Mark Ross "if law firms wish to remain the first port of call for corporate legal departments and the primary conduit for the delivery of legal services, this is predicated on their acceptance of the LPO operating model".124 LPO essentially consists of subcontracting legal work from

120 A first mover in this direction is the UK law firms Rradar. See, https://www.rradar.com/.

121 To date, the largest law firm in the world in Dentons, with more than 8500 lawyers in its ranks, followed by a relatively large number of firms with more than 2000 lawyers.

122 (Westcott 2018) See also, (Bosman and Hakanson 2017).

123 Interview with Managing Partner of Danish large law firm, 20 September 2019.

124 (Ross 2017, p. 77).

high-cost locations to sites where the same work can be executed at a significantly lower price. This often can be done by subcontracting the work to developing countries. Thus far, India, Chile, Hong Kong, Australia, the Philippines, and Sri Lanka have been the most frequent locations for outsourcing legal work, at least from the United States and the United Kingdom. Nearshoring to cheaper locations and providers that are geographically closer, including locations inside the home countries of law firms, is increasingly becoming an option.125 A more recent version of the LPO is when legal services are offered via a model that departs from the traditional law firm, for example, by using contract lawyers, process mapping, or web-based technology.126

As revealed by several informants in the interviews, several large law firms based in the United Kingdom have recently opened alternative delivery solutions teams or offices in less costly locations, such as Hull, Birmingham, Leeds, cheaper locations in the United States, and even South Africa. Notably, Clifford Chance opened its support services and knowledge management center in Delhi in 2007.127 These centers are staffed with contract attorneys, paralegals, and IT experts and their role is to execute repetitive tasks in an effective and less-costly way. More often than not, these centers make an extensive use of technology to optimize their performances.128 This means that, today, LPO has become a the standard global operating model, which combines a best-practices framework with process efficiency, quality control, consultative expertise, and enabling technology at its core. Among the areas in which LPO providers have proven to be effective and tech-savvy one can find e-discovery and document review processes, contract lifecycle management, contract review and data extraction, and legal analytics, just to name a few. This allows law firms to expand the range of services offered and deliver efficiently the appropriate level of legal services required for each type of work product.129 From the suppliers' side, an early mover for what concerns in-country outsourcing in the United States was the Dallas-based *Atlas Legal Research*. 130 The company was founded in the early 2000s by an Indian-born attorney, Abhai Dhir, immediately becoming a success, increasing its revenue by 20 percent annually since 2001. Since then, *Atlas* has hired and trained legal professionals in India to write legal briefs for American law firms at a very competitive price. Another early mover was *Pangea3*, which is now part of *Thomson Reuters Legal Managed Services*. This firm provides services such as document review and analysis, trial preparation, regulatory change management, financial trade documentation, and contract management.131 Similar services are also provided by: *Mindcrest*, founded by two former McGuire Woods partners in 2001; the Indian-based *SmithDehn* (former SDD Global Solutions Pvt. Ltd., Indian), which lists among its clients large corporations such as HBO, Calvin Klein, Sony Pictures, and BBC Worldwide;132 and *Quislex*, with offices—by them defined as "execution centers"—in Chicago, New York City, and Hyderabad, India. Notably, the office in Hyderabad, which has about 1000 full-time employees, is responsible for executing the majority of tasks, and it is divided into several multidisciplinary teams, which include data analysts, statisticians, process experts, software developers, linguists, and technologists.

In addition to this, the diffuse law firm will also outsource the technology used to agile and tech-savvy legal tech companies that will then develop tailored products for the firms. Until now,

125 (Caserta and Madsen 2019).

126 See the 2017 report of Thomson Reuters, Georgetown Law Center for the Study of the Legal Profession, and University of Oxford Said Business School entitled 'Alternative Legal Service Providers: Understanding the Growth and Benefits of These New Legal Providers' (Alternative Legal Service Providers Report 2017).

127 See, https://cliffordchance-businessservices.com/legal\_support\_centre.html.

128 Interview with Head of Innovation of large law firm, 3 December 2019.

129 See also, (Ross 2017; Beaton and Kaschner 2016). This constellation would obviously require a proper service legal agreement between the firms and the providers in order for the former to maintain control over the LPO providers.

130 http://www.atlaslegal.com/.

131 http://legalsolutions.thomsonreuters.com/law-products/solutions/legal-outsourcing-services/Pangea3.

132 http://www.smithdehnindia.com/.

the large majority of large law firms have been trying to develop their own products, in a way trying to become themselves legal-tech companies; the more savvy have signed contracts with external providers like IBM-Watson, Luminance, Kira, Elevate and others to have their own products developed in house by these external companies.133 In the long run, however, this strategy may not work entirely. As known, new technologies, especially artificial intelligence, need a large amount of data to work properly and, no matter how large, each single law firm may not be able to provide the right amount of data for achieving groundbreaking results. Thus, I argue that large law firms should outsource their technology to a number of legal-tech companies and outside consultants. This will be a win-win situation as the firms would get the tailored technology they need, and the tech-company will be able to develop large scale well-functioning products to make available for the general market. As, however, many of the technologies discussed above in this paper are at an embryonic stage and law firms have proven rather prudent in their approaches, it is difficult to substantiate more concretely the manner in which this IT-outsourcing could take place.

This model comes with some challenges. First, outsourcing raises a host of legal questions with regard to client confidentiality. The challenge is that, by storing data on third parties' servers or communicating with clients via email, lawyers give up a certain amount of control over the documents and information, yet remain obligated to safeguard their clients' information to preserve the attorney–client privilege. Second, outsourcing raises concerns related to the nature of legal work, as these services tend to treat legal services less as expert services and more as commodities. This pushes the legal profession to be more driven by the maximization of profits, rather than by the more traditional notions of justice, public good, rule of law, and fairness. This, outsourcing is likely to cause increased inequality among classes of lawyers and, perhaps, even contribute to the proletarization of part of the legal profession. Here I refer in particular to these new forms of legal, para-legal, and IT legal worker who will operate from the periphery and will be somehow excluded from pursuing more meaningful and remunerative careers. These will likely represent the poor segment of the new capitalism described by Richard Sennett in his seminal book on the new culture of capitalism.134


*4.6. Dereplication of Fractions*

One mg of each fraction A to E were resuspended in 100 μL 80% aqueous methanol, centrifuged at 13,000 rpm for 5 min, and the supernatants were transferred to UHPLC injection vials. UHPLC-HR-MS/MS analysis of the fractions was performed using a Waters Acquity I-class UPLC system interfaced with a PDA Detector and a VION IMS-qTOF (Milford, MA, USA) using electrospray ionization (ESI) in positive mode. The VION IMS- qTOF was operated with a capillary voltage of 0.80 kV, desolvation gas flow (N2) of 800 L/h, desolvation temperature of 450 ◦C, cone gas flow (N2) of 50 L/h and an ion source temperature of 120 ◦C. Data were acquired between *m*/*z* 50 and 2000 with a scan time of 0.2 s. Fragment data were acquired by ramping the energy of the collision cell from 15 to 45 V, and high and low energy data were acquired in the same run. Leucine-enkephalin was used

for internal calibration and the system was tuned to a resolution of 45,000 (FWHM). The system was controlled, and data were processed using UNIFI 1.9.4 (Waters). Chromatographic separation was achieved by injecting 3 μL of the dissolved fractions on a BEH C18 1.7 μm (2.1 × 100 mm) column (Waters) operated at 40 ◦C. The fractions were eluted with a gradient of 10% to 100% acetonitrile in water over 10 min (both containing 0.1% formic acid), followed by maintaining 100% acetonitrile until 13.5 min.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1660-3397/18/3/166/s1, Figure S1: Top: Base peak intensity chromatogram from the UHPLC-HR-MS/MS analysis of fraction C using positive electrospray. Bottom: Ion chromatogram of m/z 184. 0740 from fraction C indicating the presence of phosphocholines, Figure S2: Top: Ion chromatogram of m/z 496.3396 from fraction C showing the presence of LysoPC. Bottom: Base peak intensity chromatogram from the UHPLC-HR-MS/MS analysis of fraction C using positive electrospray, Figure S3: Top: Low energy mass spectrum of 1-Palmiotyl-sn-glycero-3-phosphocholine from fraction C. Bottom: High energy mass spectrum of 1-Palmiotyl-sn-glycero-3-phosphocholine showing fragments and mass deviations corresponding with the commercial standard, Figure S4: Top: Low energy mass spectrum of pheophorbide A from fraction D. Bottom: High energy mass spectrum of pheophorbide A showing fragments and mass deviations corresponding with the theoretical fragmentation of the database hit, Figure S5: Top: Low energy mass spectrum of hydroxypheophorbide A from fraction D. Bottom: High energy mass spectrum of hydroxypheophorbide A showing fragments and mass deviations corresponding with the theoretical fragmentation of the database hit, Table S1: The most abundant lysophosphatidylcholines in fraction C. The type indicates number of carbons and double bonds in the fatty acid moiety of the respective LysoPCs, and the retention times are given in minutes.

**Author Contributions:** C.L. and E.H.H. conceived and designed the experiments; C.L., K.H., G.R., and E.H.H. performed the experiments; C.L., K.H., G.R., and E.H.H. analyzed the data. All authors (C.L., K.H., G.R., J.H.A., A.I. and E.H.H.) co-wrote the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the "Antitumor Drugs and Vaccines from the Sea (ADViSE)" project (PG/2018/0494374).

**Acknowledgments:** We thank Massimo Perna and Mariano Amoroso for their technical support.

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


**Effects of Inflation Uncertainty on Economic Policies: Inflation-Targeting Regime Inflation-Targeting Regime**

**Effects of Inflation Uncertainty on Economic Policies:**

DOI: 10.5772/intechopen.71625

Mehmet Kenan Terzioğlu Additional information is available at the end of the chapter

Mehmet Kenan Terzioğlu

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71625

#### **Abstract**

Inflation uncertainty maintains its importance in emerging economies as well as in others. Increases in the level of inflation uncertainty constitute an important risk factor by affecting macroeconomic variables in the markets that are sensitive to price changes. The stabilization programs implemented in Turkey during 1980–2003 could not reduce the sensitivity of economic structure to inflationary shocks. Between 2003 and 2015, changes occurred, switching from high inflation to the single-digit inflation rates, in Turkey with transition to the inflation-targeting regime. Within the scope of this study, the effect of inflation uncertainty on inflation, economic growth and selected monetary-fiscal policy variables was examined using multivariate generalized autoregressive conditional heteroscedasticity (MGARCH) models. The dynamic conditional covariance model is designed to reflect the strong time-dependent correlation structure. While the inflation-targeting regime studies in developing countries focus on either the adoption or nonadoption of such a regime and its feasibility, this study evaluates the success of the regime in Turkey as an emerging economy.

**Keywords:** inflation uncertainty, inflation targeting, monetary policy, fiscal policy, MGARCH models