\r\n\tThe outcome of cancer therapy with radiation has been improving over the years due to technological progress. However, due to the biological property of cancer, current radiotherapy has limitations. Therefore, in consideration of the dynamics of tumor cells caused by radiation irradiation, attempts are being made to overcome the current drawbacks and to improve radiotherapy. It is expected that carbon ion beams, hyperthermia, oxygen effect, blood flow control, etc. will be used in the future in order to improve the treatments. This book aims to introduce research results of various radioprotective agent development research and hypoxia sensitizers.
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1. Introduction
It is currently observed that the rapid development of new electrical power sources is denominated by renewable sources for both cases: on-grid and off-grid. The main problem of off-grid stand-alone renewable energy systems (RES) is the fluctuation of power supply which can be avoided using hybrid solar/wind energy systems (HSWES) that allow improving the system efficiency, increasing power reliability, and reducing energy storage requirements for stand-alone applications [1].
In order to solve sustainability and power quality problems, the power transfer from the renewable sources to load must be managed in a proper way. Therefore an energy management process should be proposed to prevent power discontinuity or power wasting so that the loads operate properly.
A major aim of HSWES optimization is to reach the suitable size of each component and the control strategy that provide reliable, efficient, and cost-effective system. Optimization is performed by minimizing (or maximizing) an objective function using a suitable criterion such as net present cost (NPC) and/or the generated electricity price (EP). In this case the cost of avoided CO2 emissions should be taken into consideration [2].
2. Hybrid renewable energy systems
Renewable energies are intermittent sources; hence, hybrid renewable energy system (HRES) is considered an appropriate solution to support electrical requirements especially for remote areas. HRES that incorporates more than one type of renewable energy technologies in a site can help to mitigate the effect of intermittent nature that some of them exhibit and to reach a sustainable source.
As mentioned before, wind and solar systems are considered favorable sources for energy generation due to their availability and being site-power generation. However, a drawback, common to solar and wind utilization, is their unpredictable nature and dependence on weather changes; both of these energy systems would have to be oversized to make them completely reliable. Fortunately, the problems caused by variable nature of these resources can be partially overcome by integrating these two resources or more in a proper combination to form a polygene ration energy system.
HRES is an energy system that includes a number of units and equipment. Different technologies usually exist for alternative types of each of these units. Selecting the optimal alternatives is challenging; to achieve a greater knowledge of how a HRES is designed and optimized, an optimization tool should be used.
3. Optimization techniques
The optimization process is followed through an objective function (OF) with respect to some variables in the presence of constraints on those variables. The objective function is either a cost function or energy function which is to be minimized, or a reward function or utility function, which is going to be maximized [3, 4].
An optimization technique is used to find an optimized solution for a particular optimization model. “Optimum” is the word that is used to demonstrate the meaning of best, either maximum or minimum [4]. Problems dealing with the cost will require the best cost to be as less as possible. On the other hand, problems dealing with profit will see the maximum value as the best answer. There are several well-known optimization techniques depending on the model type, deterministic or stochastic, such as:
Linear programming (LP), a type of convex programming, is applied in the cases in which the OF is linear and the constraints are specified using only linear equalities and inequalities.
Second-order cone programming (SOCP) is a convex program and includes certain types of quadratic programs.
Integer programming is applied in the case that some, or all, variables of the linear solution are constrained to have an integer value. This is generally more difficult than linear programming.
Quadratic programming permits the OF to have quadratic terms, while the feasible set of solution must be identified with linear equalities and inequalities. Some specific cases of the quadratic term lead to a type of “convex programming.”
Fractional programming is concerned with the optimization of ratios of two nonlinear functions. The special class of “concave fractional programs” can be transformed to a “convex optimization” problem.
Nonlinear programming is used for the general case of the objective function and/or the constraints containing nonlinear parts. Cases of convex program affect the difficulty of the solution.
Stochastic programming is applied when some of the constraints or parameters depend on random variables.
Combinatorial optimization is applicable when the set of “feasible solutions” is, or can be, reduced to a discrete one.
Infinite-dimensional optimization is applied in the case that the set of “feasible solutions” is a subset of an “infinite-dimensional space.”
Stochastic optimization is used in the case of random function measurements or random inputs.
Robust programming is, like stochastic programming, an attempt to capture uncertainty in the data underlying the optimization problem. Robust optimization targets to find solutions that are valid under all possible realizations of the uncertainties.
Heuristics and “metaheuristics” use limited or no assumptions concerning the problem being optimized. Usually, heuristics do not guarantee that an optimal solution has to be found. In fact, heuristics are used to find approximate solutions for complicated optimization problems.
In addition to these techniques a growing interest in the application of artificial intelligence (AI) techniques to power system engineering. AI techniques, unlike strict mathematical methods, have the ability to adapt to nonlinearities and discontinuities commonly found in power systems. The best known algorithms in this class include:
Evolution programming
Genetic algorithms
Simulated annealing
Tabu search
Neural networks
4. Optimization of HRES
As power system must be sustainable, secure, and environmentally safe, the basic function of a HRES is to supply power with quality electrical energy, reliably and economically. As such, optimization plays an important role. This enables to minimize the cost of operation, initial investment, and environmental impacts and maximize reliability, quality, and efficiency.
The optimization of HRES used to analyze the system is mainly focused on two problems: (1) determine the optimal configuration of the power system and optimal type and sizing of generation units installed, and (2) design strategies for optimal dispatch, which are subject to constraints of the system meeting load requirements at minimum cost.
4.1 Costs
To reach an appropriate HRES the system should be designed according to techno-economic and environmental measures to fulfill physical and operational constraints. For cost optimization, system design seeks the configurations and control strategies that achieve the lowest total cost over the system lifetime. The lifetime cost which subjects to the system typically consists of two or more components. The life of the system is usually considered to be the life of the PV panels—which are the elements that have a longer life-span.
The OF in this case is the system net present cost (NPC), which consists of initial investment cost in addition to the discounted present worth of all future costs over the system lifetime. The system cost is the sum of all its components, e.g., PV, WT, battery, converter, and any other necessary devices, in addition to installation cost. Component costs comprise all costs: capital, replacement, operational and maintenance, and fuel consumption. Some of these costs depend on the selected control strategy.
4.2 HRES optimization model
For PV/WT/DG/battery bank system, the objective is to minimize the net present cost (NPC) under load and power constraints [5]:
MinimizeNPC=∑CPVi+∑CWj+∑CDGl+∑CBm+∑CCnE1
Subject to the constraints
∑Load≤∑EPViNPVi+∑EWj+∑EDGlE2
Power Wattagemax≤∑PCNCE3
SOCmin≤SOCt≤SOCmaxE4
where CPVi, cost of a photovoltaic module; CWj, cost of wind turbine; CDGl, cost of a diesel generator; CBm, cost of a battery; CCn, cost of a converter; NPVi, number of photovoltaic modules; NWj, number of wind turbines; NDGl, number of diesel generators; NBm, number of battery bank to be used; NCn, number of converters; PC, power of converter; EPVi, kWh generated by the ith photovoltaic module; EWj, kWh generated by the jth wind turbine; EDGl, kWh generated by the lth diesel generators; and SOC, state of charge of the battery.
The common current optimal sizing tool is the available software packages that can be helpful for real-time system integration.
5. Optimization software packages
The number of simulations and time required for calculation increases with the increase in number of optimization variables. Therefore, the selection of a quick and accurate optimization technique is very important.
Simulation software tools are the most common tools for evaluating performance of the hybrid solar/wind systems. Connolly [6] listed 67 software tools available for analysis of hybrid energy systems, studied 37 of them, and identified the suitable tools for different objectives. Some of the most widely used software tools for hybrid energy systems are summarized as follows:
5.1 iHOGA
Improved Hybrid Optimization using Genetic Algorithm (iHOGA) is a simulation and optimization software developed in C++ by the Electric Engineering Department of the University of Zaragoza, Spain [7]. This software is a tool for optimum sizing of hybrid renewable energy system. This tool uses double genetic algorithms for optimization. The main algorithm is used for the system components while a secondary algorithm is added for control strategy. The software can simulate and optimize system of any size (size from Wh to MWh even through GWh daily consumption). Optimization is achieved by minimizing total system costs through its useful lifetime. The program allows mono-objective as well as multi-objective optimization. The mono-objective and multi-objective optimizations are achieved for stand-alone and grid-connected hybrid renewable energy systems. The program modeling provides various outputs such as size of the PV generator in Wp and its ideal tilt, battery capacity in kWh, battery lifetime in years, initial investment, NPC with breakdown of the component, lowest cost of energy, and CO2 emissions of the system in CO2/kWh [7].
Dufo-López et al. used iHOGA software for the optimization of the electrical supply of a hospital existed far from the electric grid in Kalong (Democratic Republic of the Congo), which is presently powered by a diesel-battery system [8]. The results showed that adding solar photovoltaic (PV) to a diesel-battery system to supply the required load could obtain a 28% reduction in energy cost and 54% reduction in the fuel consumption reducing CO2 emissions lower than the current diesel-battery system.
Fadaeenejad et al. presented an analysis and optimization for a HRES (PV/WT/BAT), which are designed for rural electrification in Malaysia [9]. The evaluation of the performed optimization was accomplished using iHOGA software. The obtained results illustrate that the wind energy is used as a supportive source of energy for many locations in Malaysia, and the hybrid renewable energy systems are cost-effective for these rural areas.
Anita Gudelj et al. presented an optimal sizing model for hybrid energy system (HES) that aims to minimize the total cost through the useful life of the system and CO2 emissions to meet the desired consumption [10]. The iHOGA program was used to simulate the system operation and calculate technical economic parameters for each configuration. The results showed that the hybrid energy systems have considerable reductions in CO2 emission and cost of the system. Using a diesel generator as a backup source, for the PV/WT/battery system, was found to be the best solution to guarantee the reliable supply without any shortage of the required load under the weather data change.
5.2 HOMER
The National Renewable Energy Laboratory (NREL) introduced a Hybrid Optimization Model for Electric Renewable (HOMER) package. HOMER uses hourly load and weather data inputs to perform hourly simulations for techno-economic analysis of hybrid energy systems [11]. HOMER performs three tasks: simulation, optimization, and sensitivity analysis. It facilitates the optimization of simulated renewable energy systems to minimize NPC for a given set of constraints.
Mustafizur Rahman et al. [12] suggested seven scenarios of combining hybrid renewable energy technologies with diesel generator to minimize the economic and environmental concern effects of its use. The suggested scenarios were (100, 80, 60, 50, 35, 21, and 0%) renewable resource penetration. A case study for the remote community of Sandy Lake, Ontario, was conducted. The different scenarios modeled are developed by using HOMER software. The aim of this study was to find the best combination of hybrid renewable energy systems from the available resources for a particular off-grid location in Canada. The results showed that using 80% renewable energy scenario can achieve the demand with 72% higher COE but 83% lower CO emissions than 0% renewable fraction—100% diesel-battery scenario.
In a similar study, Ngan et al. [13] focused on the technical and economic feasibility of “the hybrid energy systems (PV/WT/DG)” in a southern city of Malaysia using HOMER simulation software. They considered seven different system configurations: stand-alone diesel generator system, hybrid PV-diesel system, PV-diesel system with battery storage, hybrid wind-diesel system, wind turbine-diesel system with battery storage, wind-solar-diesel system, and wind-solar-diesel system with battery storage.
Targeting to study technical and economic performance of wind/diesel/battery (W/D/B) system supplying a remote small gathering of six families, HOMER package was used [14]. Net present cost (NPC) and cost of energy (COE) are used as economic criteria, while % of power shortage is the measure of performance. Optimum system configurations are estimated for two sites. Simulation results showed that W/D/B systems are economical for the assumed community sites as the price of generated electricity was about 0.308 $/kWh, without taking external benefits into considerations. W/D/B systems were found to be more economical than diesel-alone system.
A case study of the performance and optimization of a HRES supplying a water desalination system for irrigating a small greenhouse hydroponic cultivation was presented by Khatab et al. [15]. The study presented optimization of two hybrid systems: photovoltaic/wind turbine (PV/WT) with and without backup diesel generator. The results showed that COE of PV/WT system is less than that of PV/WT/diesel, while there is no capacity shortage in the case of PV/WT/diesel.
5.3 RETScreen
It is developed by Natural Resources Canada to evaluate the energy production, costs, emission reduction, and financial viability for various types of renewable and nonrenewable energy systems [16]. It performs economical comparison between conventional system and proposed system. A study examined the potential for a 10-MW PV power plant in Abu Dhabi using RETScreen modeling software to forecast the produced energy, financial feasibility, and GHG emissions reductions [17]. Initial results showed high energy production potential and saving a high amount of tons of GHG emissions annually.
5.4 HYBRID2
This software package is developed by the National Renewable Energy Laboratory (NREL) of the United States Department of Energy in cooperation with the University of Massachusetts. This hybrid simulation software can run simulation for time intervals from 10 mintues to 1 hour. The NREL recommends the HYBRID2 for the thermal loads [18].
5.5 TRNSYS
TRNSYS is a transient system simulation program developed by the Solar Energy Laboratory, University of Wisconsin-Madison, USA. It has a modular structure in which components of the system are specified by the user [19]. It can simulate almost all thermal and renewable power generation systems.
5.6 Other applications of different packages
A review of the optimization techniques used to select HES that minimize initial and operating cost was presented by Erdinc and Uzunoglu [20]. The compared techniques were (GA), “simulated annealing” (SA),“particle swarm optimization” (PSO), and HOMER. The approach for component sizing is based on demanded load, renewable resources availability, and climatic conditions.
For a touristic resort in Malaysia, Hossaina et al. [21] suggested a stand-alone HRES that includes WT, PV, DG, converter, and battery as energy sources to replace the existing diesel generators. The estimated daily average and peak load were 13,048 and 1185 kW, respectively. The system techno-economic was achieved using HOMER software, and the results exhibited that the hybrid system has lower NPC and COE than the existing diesel system.
In a similar study, Olatomiwa et al. [22] investigated different (PV, WT, and DG) power configurations in six “geopolitical” zones of Nigeria, also by HOMER [23]. The result denoted that the PV/DG/battery system configuration is the optimum configuration in the cases of diesel fuel price of $1.1–1.3/l, exhibited lower fuel consumption, and reduced CO2 emission.
“HOMER” was also applied to investigate the possibility of providing 200 households in remote area in Ethiopia with electricity using HSES [24]. The results revealed that PV/DG/battery system is the most “cost-effective” using load following strategy. The authors concluded that this study could be considered applicable for similar climatic condition regions.
Another comparable feasibility analysis of (HRES) supplying load requirements of a rural village, of 50 families, in Bangladesh, far from the grid was performed using “HOMER package” [25]. The “annual average load” was 213 kWh/day; the results indicated that for this location, load profile of the feasible system is also PV/WT/battery where the NPC had a total of $224,345 and COE of 0.161 $/kWh with no CO2 emission.
A fuzzy logic power controller was proposed by Alam et al. [26] to provide continuous power supply, from a hybrid WT/PV/fuel cell power system with battery, for remote area. The simulated system configuration was 20 kW WT, 80 kW PV array, and 10 kW fuel cell. Excess power was directed to the batteries first and then to the electrolyzer. In the case the optimum system, the results showed that power shortage had reached 254 kWh/year, which represented a high percentage of the total load. Also the estimated cost of energy was very high (1.045 $/kWh).
Ajao et al. [27] performed an economic analysis of PV/WT system for a Nigerian area. The authors concluded that the proposed system is expensive because of high capital and installation costs. The authors did not take into consideration the reduction of greenhouse gas emission which would improve the cost-effectiveness of the system.
Seeking the optimum design of economically feasible HES to feed a load which had seasonal variations, Fulzele et al. used iHOGA to simulate and optimize the system [28]. The results showed that 99% of the required load was covered by the system, subject to operational constraints and control strategies. Nevertheless, the results did not take into consideration that the excess energy was about 25% and minimizing this value would reduce the cost of energy (COE).
6. Energy management
Energy management is considered as an optimization action. Energy management increases usable energy, decreases wasted energy, and has the additional benefits of optimizing energy systems and improving their reliabilities.
The electrical power generated by renewable sources such as wind and solar power is affected by environmental conditions resulting in problems in load side. When there is no sun or the weather is cloudy, the power amount to be generated by solar energy changes. Accordingly, wind does not blow at the same speed all the time; it is discontinuous. Henceforth, energy amount to be generated from these sources is variable. Energy management processes are developed to prevent problems like discontinuities that occur due to either weather changes or sudden load changes.
Different methodologies and techniques used to develop a successful energy management strategy, for both stand-alone hybrid renewable energy systems and the grid-connected hybrid renewable systems, were investigated by Olatomiwa et al. [22]. The authors focused on energy management based on “linear programming,” “intelligent techniques,” as well as energy management by “fuzzy logic controller.” The authors emphasized that selecting the suitable energy management strategy is necessary to control the energy flow in the system that increases reliability, decreases electricity shortage, reduces the “COE,” and increases the system lifetime.
In a study that investigated the performance of various possible configurations using iHOGA software, the achieved optimum configuration was further improved by adapting the daily load pattern to the periods of high renewable generated energy to increase direct energy utilization rather than charging batteries [29]. This will result in effective minimization of battery bank size.
7. Case study in an Egyptian farm
The study objective was to design and simulate HSES for remote area in Egypt. The study was performed using iHOGA simulation and optimization package to decide on the optimal size of each component and control strategy. The input data for the optimization are weather data of the selected location, nominated system component cost, and technical parameters. Financial parameters, interest and inflation rates, installation, and operational costs are also included. The proposed system components are PV/WT/batteries/DG/inverter and charge regulator. The suggested load in this case study is energy required for a desalination unit (DU). The system is installed in NRC farm in Noubarya. The considered system configuration is shown in Figure 1.
Figure 1.
The system configuration.
NRC farm is in a remote area that is located between 30°40′0” N and 30°4′0″ E. The average temperatures for winter and summer are about 14 and 28°C, respectively. The farm is a research pilot plant for agriculture, animal, and fish production. Frequent electricity shortage is observed due to instability of low-voltage grid power in the area.
7.1 Load profile (base case)
In this case study, the HSES provides a reverse osmosis desalination unit (DU) with electricity. The required daily desalinated water is about 60–65 m3. The required power for the DU is the sum of powers required for three types of pumps included in the DU: “5 HP high-pressure pump” (3728 W), “distribution pump” (1000 W), and a “feed pump” (1870 W in the case of feeding rate is 7 m3/hour). To produce 60–65 m3/day, the DU should be fed by 110 m3 of brackish water per day. The first suggested load profile in this study; referred to as base case, the high-pressure pump, the distribution pump, and feed pump are designated to work simultaneously. Hence, the peak load requirement is about 6.6 kW continuously from 00:00 to 16:00, and the average estimated daily energy consumption is 105.6 kWh (Figure 2).
Figure 2.
DU base case load profile (base case).
7.2 Resource input data
The input climatic data for the proposed site are obtained from NASA Surface Meteorology and Solar Energy [30]. Table 1 represents the monthly average of solar radiation and wind speed data for the selected area.
As mentioned above, the system components are PV, WT, inverter, batteries, and DG. A number of monocrystalline and polycrystalline PV modules (in the range of 100–280 W/panel) were used in the simulation to select the suitable size. The initial panel cost is in the range of $143–455, while O&M cost of each panel is 1.43–4.55$/year. The panels’ lifetime is considered to be 25 years. The WT types used in simulation are “Bornay” and “Hummer,” both of 3–30 kW power range, and its hub height is considered to be between 15 and 18 m. The initial cost of WT is between $9821 and 44,200, its replacement costs $7800–33,800, and O&M cost $196–884/year. The lifetime of “Bornay” and “Hummer” are assumed to be 15 and 20 years, respectively. A backup DG is 3–4 kVA, and the battery bank is in the range of 180–3360 Ah with 80% depth of discharge used. The system also comprises an inverter which is scaled according to the maximum peak load. The inverter type is ACME: 8000VA CARG. The above-stated values are attained from iHOGA database.
7.4 Control strategies
The software package used in this study is iHOGA, which offers two control strategies: load following and cycle charging strategy. In the first the priority is to meet the load at any given time. Hence, if the generated power from the HES is not enough to cover the whole load, the battery covers the rest of the demand. If the battery bank cannot cover the whole rest of the demand, the DG will operate.
In “cycle charging strategy,” if the total (PV&WT) generated energy is greater than the load requirements, the excess energy charges the batteries. When batteries’ state of charge (SOC) reaches its maximum value, the charging process is set off, while if (PV&WT) energy is lower than the load, the rest is covered by the battery bank. If the battery charge drops to its minimum SOC, the controller unit sets off discharging process and turns DG on to cover the unmet load. As it is well known, it is better to run the DG at its rated power to reach higher efficiency of fuel consumption; DG will serve the load and the extra power and, if any, will be used to charge the batteries to its maximum SOC.
Both of the above strategies are examined to select the optimal strategy for the given system constraints.
7.5 Objective function
The main target of the suggested system design is to reach the optimum solution of a HRES in terms of economic and technical conditions subject to the operational strategies and physical constraints. In this method, the possible optimum system configuration is the one that satisfies the user-defined constraints in accordance with the objective function. The objective function is to minimize NPC which consists of initial cost, replacement cost, maintenance, and running cost of system components like PV, WT, DG, batteries, converter, and etc. [10, 12, 31].
Objective function:
E5
where Tc is the total capital cost of different components and Tr is the total replacement cost and TO&M is the total cost of operation and maintenance in dollars.
There are many constraints that are considered to ensure that the generated electricity would cover the load such as the minimum renewable fraction (75%), levelized cost of energy (5 $/kWh), and the maximum percentage of annual unmet load which is defined to be 5%.
8. Results and discussion of base case
The suggested system is simulated to reach the optimum value of the selected objective function under the following constraints: minimum renewable fraction (RF) 75%, levelized cost of energy 5 $/kWh, and the maximum percentage of annual unmet load 5%. The simulated optimization results (for base case load) are shown in Figure 3.
Figure 3.
Results of NPC as a function of generations.
Figure 3 exhibits the estimated optimum NPC and CO2 emission of a number of simulation runs. The optimization results of the base case showed a minimum NPC of $162,034, COE of 0.17 $/kWh, and unmet required load of 1.3%. HSES optimum configuration is 53 parallel series of PV panels, 4 modules each of 100Wp rated power, 24 batteries connected in series each of 1340 Ah, 1 WT of 14.7 kW at 14 m/s, 8 kVA inverter, and 3 kVA (AC) diesel generator. Figure 4 illustrates the annual distribution of energy generation.
Figure 4.
Annual distribution of energy.
It is observed in Figure 4 that almost all the yearly demand, except 495.8 kWh/year, is fulfilled by the HSES generated energy, which account for less than 1.5% of total load, the CO2 emissions of 11,950 kg/year. It could be also observed that the energy charging batteries are 10,768 kWh/year, (about 21% from the total generated power), and the excess energy is 8278 kWh/year, (about 16%).
The total generated energy is about 50,800 kWh/year, while the total load that is directly supplied by energy sources is 28,386 kWh/year, so the utilization of the energy sources is about 55.9%. As the efficiency of both inverter and battery charger is high, 98 and 95%, respectively, then the main losses result from battery charging and discharging efficiency which is 85%. As the charging and discharging energy amounts to 20,407 kWh/year, then energy losses are about 3000 kWh. The cost of different HSES simulated components are shown in Table 2.
Cost element
Initial cost ($)
Percentage (%)
PV panel cost
37,282
23
WT cost
27,246
16.8
DG cost
21,667
13.3
Battery bank cost
36,940
22.8
Inverter cost
10,952
6.7
DG fuel cost
16,687
10.3
Charge reg. cost and AUX
11,256
6.4
Table 2.
Component costs of the optimized HSES.
It could be seen from the above table that the major cost items are PV panels and “battery bank” which represent about 23 and 22.8% of the total NPC. The high cost of the “battery bank” indicates that power generation profile does not match the load pattern; therefore a considerable part of generated energy has to be stored to cover the load when generated energy is not enough.
Regarding energy management, the main objective is to cover the DU load while minimizing the NPC and accordingly the cost of water desalination. From the results of the base case simulation, it is clear that, at some periods, a considerable amount of the generated energy does not match the load profile; therefore, it is directed to charge batteries. Hence, the amounts of energy charging the batteries and “excess energy” are excessive in some months as exhibited in Figures 5 and 6. Reducing these values would improve the system performance; hence, the configuration should be further adapted by means of load pattern managing. Load profile management could be achieved through matching its pattern with the power generation profiles. This would decrease the number and cost of batteries and consequently the total NPC.
Figure 5.
Monthly average energy charging battery.
Figure 6.
Monthly average excess energy.
Considering the hourly simulation results for the highest months of excess energy and energy charging battery amounts, different load patterns were proposed and simulated, of which the following four arrangements represented the most promising patterns to increase the direct utilization of the generated energy as shown in Figure 7.
Figure 7.
Suggested load profiles.
As exhibited in Figure 7, the suggested load profile 1 proposed that all pumps are turned on from 05:00 to 21:00 requiring 6600 kWh. Load profile 2 schedule is based on the assumption that the “feed pump” is running from 00:00 to 08:00, while the “high-pressure” and “distribution” pumps are scheduled from 08:00 to 16:00. Finally all pumps work simultaneously from 16:00 to 24:00 as shown in Figure 8. This pattern is scheduled to fit high power period that is generated from the PV panel in the middle of the day and also the wind power at the night which is the period of high wind speed.
Figure 8.
Effect of suggested load profiles on NPC, battery cost, and energy battery charging.
“Load profile 3” is arranged as feed pump running from 00:00 to 06:00 and from 22:00 to 24:00, while “high-pressure” and “distribution” pumps begin to work simultaneously, along with the “feed pump,” from 08:00 to 16:00. The feed pump is switched off from 06:00 to 08:00 and 16:00 to 22:00, while the other two pumps remain operating. In the case of proposed “load profile 4,” the feed pump schedule is running three periods: from 00:00 to 04:00, from 20:00 to 24:00, and from 04:00 to 08:00. The “high-pressure” and “distribution” pumps start working when the feed pump is switched off except from 08:00 to 16:00 when all the pumps are working simultaneously. This profile is supposed to be fitting the period of high PV and WT energy generation to increase direct energy utilization.
The simulated optimization results of base case and the suggested four load profiles are exhibited in Tables 3 and 4.
Case no.
NPC ($)
COE ($/kWh)
PV cost ($)
WT cost ($)
Battery cost ($)
Base case
162,034
0.17
37,282
27,246
36,940
Profile 1
138,249
0.15
34,545
27,246
21,274
Profile 2
149,266
0.16
31,808
27,246
28,692
Profile 3
137,694
0.15
30,440
27,246
18,444
Profile 4
137,011
0.15
30,440
27,246
18,451
Table 3.
Cost results of the suggested load profiles ($).
Case no.
NPC ($)
Charge battery (kWh/year)
Excess energy (kWh/year)
Base case
162,034
10,768
8278
Profile 1
138,249
6231
6312
Profile 2
149,266
8768
4544
Profile 3
137,694
5294
3590
Profile 4
137,011
5241
3665
Table 4.
Results of the suggested load profiles.
It is noticed from the summarized results in the above tables that load profile 4 has the lowest NPC and COE (137,011$ and 0.15 $/kWh) among the four suggested profiles in addition to minimum value of energy charging the batteries (5241 kWh/year). The suggested load profiles also demonstrate the effect of decreasing the energy charging the batteries on the NPC as illustrated in Figure 8.
It is clear from Figure 8 that the lowest battery charging energy is that of load profile 4 (5241 kWh) which is the case of lowest NPC configuration (137,011 $). Table 5 exhibits the energy utilization, battery charging energy, and energy loss as a percentage of the total energy. It also exhibits battery cost as a percentage of the total energy system costs.
Case no.
Utilization (%)
Energy charging batteries (%)
Energy loss (%)
Battery cost (%)
Base case
55
27
22
22.8
Profile 1
66
16
18
15.4
Profile 2
65
22
13
19.2
Profile 3
73
13
14
13.4
Profile 4
73
13
14
13.4
Table 5.
Load profiles’ results (percentages).
The above tables showed that decreasing excess energy and energy charging batteries reduced NPC cost. Increased utilization of the location resources is achieved through fitting the peaks of demanded load with the periods of high power generation which affected energy components, reducing generation and storage components’ sizes.
9. Conclusions and recommendations
The optimization results for HRES under study, considered as the base case, are NPC is $162,034, COE is 0.17 $/kWh, and the unmet load (energy shortage) is 1.3% of the total required energy, while the renewable fraction is about 75%. However, this optimum configuration showed high values of energy charging batteries (which means higher battery bank capacity) and excess energy which represented 21 and 16%, respectively. At the same time, the total load that is directly supplied by energy sources was only 55% of total generated energy. This indicated that the load profile does not match the renewably generated energy; hence, different load scenarios were investigated. The simulation results of the best reached load pattern, referred to as “load profile 4,” are as follows:
Maximizing direct use of renewable generated energy causes reduction in system component sizes. The results showed that “load profile 4” has the lowest NPC and COE values (137,011 $ and 0.15 $/kWh) and minimum energy charging batteries (5241 kWh/year), which suggests that NPC and COE are directly proportional to energy charging battery.
Managing load pattern to reach the best fitted profile has decreased NPC by 15.4%, charging energy battery by 51.3%, the cost of batteries by 50%, COE by 11.7%, and the excess energy by 55.7%, while the utilization of the energy sources is increased by 18%, compared to the base case configuration.
In short, “load profile 4” caused significant improvement on the following parameters:
NPC has decreased by 15.4%.
Battery charging energy has decreased by 51.3%.
The cost of batteries has decreased by 50%.
The cost of energy has decreased by 11.7%.
The excess energy has decreased by 55.7%.
The utilization of the energy sources is increased by 18%.
Taking environmental impacts of CO2 into consideration will further decrease the cost of system generated energy.
\n',keywords:"hybrid energy system, optimization, hybrid energy packaged, energy management",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69047.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69047.xml",downloadPdfUrl:"/chapter/pdf-download/69047",previewPdfUrl:"/chapter/pdf-preview/69047",totalDownloads:312,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"July 27th 2019",dateReviewed:"August 12th 2019",datePrePublished:null,datePublished:"March 25th 2020",dateFinished:"September 13th 2019",readingETA:"0",abstract:"Solar and wind energy systems are considered as promising power-generating sources due to their availability and advantages in local power generation. However, a drawback is their unpredictable nature. This problem can be partially overcome by integrating these two resources or more in a proper combination to form a hybrid energy system. Nevertheless, the harmonization of different energy sources, energy storage, and load requirements is a challenging task. Thus, the performance of various possible configurations has to be investigated to reach the optimum combination using a simulation program. The number of simulations and time required for calculation increases with the increase in number of optimization variables. Therefore, the selection of a quick and accurate optimization technique is very important. Different software packages, such as HOMER and iHOGA, were developed, where each of them is based on a different optimization algorithm.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69047",risUrl:"/chapter/ris/69047",book:{slug:"modeling-simulation-and-optimization-of-wind-farms-and-hybrid-systems"},signatures:"Mervat Abd El Sattar Badr",authors:[{id:"309967",title:"Prof.",name:"Mervat",middleName:null,surname:"Badr",fullName:"Mervat Badr",slug:"mervat-badr",email:"dr_mabadr@yahoo.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Hybrid renewable energy systems",level:"1"},{id:"sec_3",title:"3. Optimization techniques",level:"1"},{id:"sec_4",title:"4. Optimization of HRES",level:"1"},{id:"sec_4_2",title:"4.1 Costs",level:"2"},{id:"sec_5_2",title:"4.2 HRES optimization model",level:"2"},{id:"sec_7",title:"5. Optimization software packages",level:"1"},{id:"sec_7_2",title:"5.1 iHOGA",level:"2"},{id:"sec_8_2",title:"5.2 HOMER",level:"2"},{id:"sec_9_2",title:"5.3 RETScreen",level:"2"},{id:"sec_10_2",title:"5.4 HYBRID2",level:"2"},{id:"sec_11_2",title:"5.5 TRNSYS",level:"2"},{id:"sec_12_2",title:"5.6 Other applications of different packages",level:"2"},{id:"sec_14",title:"6. Energy management",level:"1"},{id:"sec_15",title:"7. Case study in an Egyptian farm",level:"1"},{id:"sec_15_2",title:"7.1 Load profile (base case)",level:"2"},{id:"sec_16_2",title:"7.2 Resource input data",level:"2"},{id:"sec_17_2",title:"7.3 System description",level:"2"},{id:"sec_18_2",title:"7.4 Control strategies",level:"2"},{id:"sec_19_2",title:"7.5 Objective function",level:"2"},{id:"sec_21",title:"8. Results and discussion of base case",level:"1"},{id:"sec_22",title:"9. Conclusions and recommendations",level:"1"}],chapterReferences:[{id:"B1",body:'Patel MR. Wind and Solar Power Systems. CRC Press LLC; 1999. 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Renewable Energy Focus. 2018;25:48-56'},{id:"B30",body:'NASA Surface meteorology and Solar Energy: RETScreen Data. Available from: https://eosweb.larc.nasa.gov/cgi-bin/sse/retscreen.cgi?email=&step=1&lat=30.6667&lon=30.0667&submit=Submit'},{id:"B31",body:'Yazdanpanah M-A. Modeling and sizing optimization of hybrid photovoltaic/wind power generation system. Journal of Industrial Engineering International. 2014:10-49'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mervat Abd El Sattar Badr",address:"dr_mabadr@yahoo.com",affiliation:'
Professor, National Research Centre (NRC), Egypt
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Renukappa",authors:[{id:"227309",title:"Dr.",name:"Rashmi",middleName:null,surname:"Aradhya",fullName:"Rashmi Aradhya",slug:"rashmi-aradhya"},{id:"227469",title:"Dr.",name:"Nijagal M.",middleName:null,surname:"Renukappa",fullName:"Nijagal M. Renukappa",slug:"nijagal-m.-renukappa"}]},{id:"64535",title:"Optimization of Functionally Graded Material Structures: Some Case Studies",slug:"optimization-of-functionally-graded-material-structures-some-case-studies",signatures:"Karam Maalawi",authors:[{id:"18593",title:"Prof.",name:"Karam",middleName:"Youssef",surname:"Maalawi",fullName:"Karam Maalawi",slug:"karam-maalawi"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"62502",title:"Thiophene S-Oxides",doi:"10.5772/intechopen.79080",slug:"thiophene-s-oxides",body:'\n
\n
1. Early history of oxidation reactions of thiophenes: cycloaddition reactions of thiophene S-oxides prepared in situ in absence of Lewis acids
\n
In the first half of the 20th century, considerable effort was devoted to the oxidation of the heteroaromatic thiophene (1) with the understanding that the oxidation of thiophene to thiophene S,S-dioxide (2) (Figure 1) would be accompanied by the loss of aromaticity [1, 2]. The non-substituted thiophene S,S-dioxide (1) is not very stable in the pure state [3], but undergoes a slow dimerization with concurrent extrusion of SO2 from the primary cycloadduct (4) [4], leading to 5 (Scheme 1). Only much later were the properties and reactivity of pure, isolated non-substituted thiophene S,S-dioxide (2) described [5].
\n
Figure 1.
Structure of thiophene (1) and oxygenated thiophenes 2 and 3.
\n
Scheme 1.
Dimerisation of unsubstituted thiophene S,S-dioxide (2).
\n
Much of the early work on the oxidation of thiophenes to thiophene S,S-dioxides involved hydrogen peroxide (H2O2) as oxidant, later meta-chloroperoxybenzoic acid (m-CPBA). That thiophene S-oxide was an intermediate in such oxidation reactions [6, 7, 8] was evident from the isolation of so-called sesquioxides as dimerization products of thiophene S-oxides [9, 10, 11, 12]. Here, the thiophene S-oxide acted as diene with either another molecule of thiophene S-oxide or thiophene S,S-dioxide acting as ene [9, 10, 11, 12] to give cycloadducts 6–8 (Figure 2). Thiophene S-monoxide (3) as an intermediate in the oxidation process of thiophene (1) to thiophene S,S-dioxide (2) could not be isolated under the conditions.
\n
Figure 2.
Sesquioxides obtained by dimerization of elusive thiophene S-oxide and by cycloaddition of thiophene S-oxide to thiophene S,S-dioxide.
\n
Nevertheless, the idea that a thiophene S-oxide intermediate could be reacted with an alkene of choice led Torssell [13] oxidize methylated thiophenes with m-CPBA in the presence of quinones such as p-benzoquinone (12). This gave cycloadducts 13 and 14 (Scheme 2) [13]. Further groups [11, 12, 14, 15, 16, 17, 18, 19] used this strategy to react thiophene S-oxides such as 11, prepared in-situ with alkenes and alkynes in [4 + 2]-cycloadditions (Schemes 3 and 4). In the reaction with alkenes, 7-thiabicyclo[2.2.1]heptene S-oxides such as 13 were obtained, while the reaction of thiophene S-oxides with alkynes led to cyclohexadienes and/or to aromatic products, where the initially formed, instable 7-thiabicyclo[2.2.1]hepta-2,5-diene S-oxide system 21 extrudes its SO bridge spontaneously (Scheme 4). A number of synthetic routes to multifunctionalized cyclophanes 32 [17], aryl amino acids 25 [16] and to crown ethers 29 [15] (Scheme 5) have used the cycloaddition of thiophene S-oxides 19, created in-situ, as a key step. The formation of the 7-thiabicyclo[2.2.1]heptene S-oxides (such as 13, 18) proceeds with stereocontrol. The cycloadditions yield predominantly endo-cycloadducts, with the oxygen of the sulfoxy bridge directed towards the incoming dienophile, exhibiting the syn-π-facial stereoselective nature of the reaction (see below for further discussion of the stereochemistry of the cycloadducts). Thiophene S,S-dioxides 2 possess an electron-withdrawing sulfone group, which leads both to a polarization and to a reduction of the electron density in the diene [20]. This results in a decrease of the energy of the HOMO as compared to identically substituted cyclopentadienes [20]. Thiophene S,S-dioxides 2 are sterically more exacting than C5 non-substituted cyclopentadienes, with the lone electron pairs on the sulfone oxygens leading to adverse non-bonding interactions with potentially in-coming dienophiles of high π-electron density. Thus, thiophene S,S-dioxides 2 often require higher temperatures [21, 22] in cycloaddition reactions than identically substituted cyclopentadienes. Recent frontier molecular orbital calculations at the HF/6-311++G(d,p)//M06-2X/6-31+G(d) level theory have shown that both HOMO (by 0.5 eV) and LUMO (by 0.4 eV) in thiophene S-oxide (3) are slightly higher in energy than in thiophene S,S-dioxide (2) [23].
\n
Scheme 2.
Thiophene S-oxide (11), created in situ, reacts in Diels-Alder type fashion with p-benzoquinone (12).
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Scheme 3.
Cycloaddition of thiophene S-oxides, prepared in situ, with alkenes.
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Scheme 4.
Cycloaddition of thiophene S-oxides (19), prepared in situ, with alkynes.
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Scheme 5.
Cycloaddition of thiophene S-oxides prepared in situ—applications in the synthesis of functionalized aminocarboxylic acids 25, crown ethers 29 and cyclophanes 32.
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Oxidation of the thienyl-unit in 33 leads to an intramolecular cycloaddition, where indanones 34 are obtained (Scheme 6) [24].
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Scheme 6.
Intramolecular cycloaddition of in situ prepared thiophene S-oxide 34.
\n
\n
\n
2. Cycloaddition reactions of thiophene S-oxide prepared in situ in the presence of Lewis acids: thiophene S-oxides are isolated
\n
Yields of cycloadducts have been found to be much higher, when oxidative cycloaddition reactions of thiophenes are carried out with meta-chloroperoxybenzoic acid (m-CPBA) or with H2O2 at lower temperatures such as at −20°C in the presence of a Lewis acid catalyst such as BF3·Et2O [11, 12, 25, 26] (Scheme 7) or of trifluoroacetic acid (CF3CO2H) [27]. Electron-poor dienophiles such as tetracyanoethylene, acetylene dicarboxylates, quinones, maleimides and maleic anhydride and mono-activated enes such as cyclopentenone and acrolein were used in these reactions.
\n
Scheme 7.
Oxidative cycloaddition of thiophene 36 to naphthoquinone (37) in the presence of BF3.Et2O.
\n
Under the conditions m-CPBA/BF3·Et2O, the cycloadditive transformation of thiophene S-oxides, prepared in situ, was used in the synthesis of new cyclophanes such as 39 (Scheme 8) [25]. A series of 2,3-bis(hydroxyphenyl) substituted 7-thiabicyclo[2.2.1]hept-2-ene S-oxides as potential estrogen receptor ligands were prepared by oxidative cycloaddition of 3,4-bis(hydroxyphenyl)thiophenes in the presence of BF3·Et2O [28]. Also the key step in Yu et al.’s [27] synthesis of steroidal saponins 44, closely related to the E-ring areno containing natural products aethiosides A–C, is a BF3·Et2O catalyzed oxidative cycloaddition of the thieno-containing steroidal saponin 42 (Scheme 9) [26]. Furthermore, Zeng and Eguchi [29] were able to functionalize C60 (46) by cycloaddition with in-situ produced 2,5-dimethylthiophene S-oxide (45) [29, 30] (Scheme 10). Nevertheless, sterically hindered thiophenes are more difficult to be subjected to the oxidative cycloaddition reactions (Figure 3).
\n
Scheme 8.
Preparation of multifunctionalized cyclophane 41 by oxidative cycloaddition of thiophenophane 39 in the presence of BF3.Et2O.
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Scheme 9.
Preparation of aethiosides A–C (44a–c) by oxidative cycloaddition of thienosteroidal sapogenin 42.
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Scheme 10.
Cycloaddition of 2,5-dimethylthiophene S-oxide (45), prepared in situ, to C60 (46).
\n
Figure 3.
Orthothiophenophanes 48 and 49 do not allow for enough reaction volume and do not undergo oxidative cycloadditions with either alkynes or alkenes under the conditions (m-CPBA, BF3.Et2O, CH2Cl2) [31].
\n
\n
\n
3. Preparation and isolation of pure thiophene S-oxides
\n
Thiophene S-oxides could be isolated in pure form as side-products in a number of oxidative cycloaddition reactions using alkylated thiophenes as substrates run with m-CPBA in the presence of BF3·Et2O [11, 12]. Nevertheless, the first ascertained thiophene S-oxide (51) isolated in pure form came from the oxidation of the sterically exacting 2,5-bis-tert-butylthiophene (50) in absence of a Lewis acid or an added protic acid. 2,5-Bis-tert-butylthiophene S-oxide (51) could be isolated in 5% yield [32] (Scheme 11).
\n
Scheme 11.
Isolation of 2,5-bis-tert-butylthiophene S-oxide 51 by simple thiophene oxidation with meta-chloroperoxybenzoic acid (m-CPBA) [32].
\n
Previous to the isolation of thiophene S-oxides in pure form, based on UV-spectroscopic measurements, Procházka [33] had claimed that the parent thiophene S-oxide (3) could be prepared by double elimination from 3,4-dimesyloxy-2,3,4,5-tetrahydrothiophene S-oxide (53) and studied in solution. While subsequently the latter part of the assertion was thrown into doubt, the isolation of sesquioxides 7/8 from the reaction indicated at least the presence of thiophene S-oxide under these conditions [33] (Scheme 12).
\n
Scheme 12.
In situ preparation of parent thiophene S-oxide (3) by an elimination reaction [33].
\n
Interestingly, a toluene solution of η5-ethyltetramethylcyclopentadienyl-η4-tetramethylthienyl rhodium complex [Cp*Rh(η4-TMT)] (54) can be oxidized with dry oxygen to [Cp*Rh(TMTO)] (56), which features a η4-coordinated thiophene S-oxide ligand. Complex 56 was isolated and an X-ray crystal structure was carried out. Alternatively, [Cp*Rh(η4-TMT)] (54) can be oxidized electrochemically to [Cp*Rh(η4-TMT)]2+ (55), which can also be obtained by protonation of [Cp*Rh(TMTO)] (56). Reaction of [Cp*Rh(η4-TMT)]2+ (55) with potassium methylsilanolate (KOSiMe3) leads back to [Cp*Rh(TMTO)] (56) [34] (Scheme 13).
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Scheme 13.
Oxidation of [Cp*Rh(η4-TMT)] (54) to [Cp*Rh(TMTO)] (56) [34].
\n
The reaction of the cationic transitory ruthenium complex [Ru(C6R6)(C4R4S)]+ (57) with hydroxyl anion (OH−) gives Ru(C6H6)(C4R4SO) (58) [35] (Scheme 14). Here, in contrast to the complex [Cp*Rh(TMTO)] (56), the thiophene S-oxide ligand in Ru(C6H6)(C4R4SO) (58) is not stable, but opens to an acetylpropenethiolate. Stable osmium thiophene S-oxide complexes of type (cymene)Os(C4Me4S=O) have also been prepared [36]. In neither of the cases, was it tried to decomplex the thiophene S-oxide ligand.
\n
Scheme 14.
Base hydrolysis of [Ru(C6R6)(C4R4S)]+ (57) [34].
\n
In the 1990s, two main synthetic methodologies were developed to prepare thiophene S-oxides 63. The first involves the reaction of substituted zirconacyclopentadienes 62 with thionyl chloride (SOCl2), developed by Fagan et al. [37, 38] and by Meier-Brocks and Weiss [39]. Typically, tetraarylzirconacyclopentadienes 62a can be synthesized easily by reacting CpZrCl2 (59), n-BuLi and diarylethyne (61a) in one step (Scheme 15). This strategy was followed by Tilley et al. [40, 41] in their synthesis of substituted thiophene S-oxides. Miller et al. published results for a synthesis of 2,5-diarylthiophene S-oxides (63b) along the same lines, using ethynylarene (61b) [42].
\n
Scheme 15.
Synthesis of tetraarylthiophene S-oxides 63a/b by reaction of tetraarylzirconacyclopentadienes 62a/b with SOCl2.
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The other methodology involves an oxidation of a thiophene with either a peracid in the presence of a Lewis acid such as titanium tetrachloride (TiCl4) [43] or boron trifluoride etherate (BF3·Et2O) [44, 45] or with hydrogen peroxide in the presence of a protonic acid such as trifluoroacetic acid [46, 47] (Scheme 16). Also, the use of the reaction system H2O2 in presence of NaFe(III) ethylenediaminetetraacetate/Al2O3 has been reported [48, 49] (Scheme 16) as has been the use of the reaction system [(C18H37)2(CH3)2N]3[SiO4H(WO5)3] [50]. The thiophene S-oxides 65, suitably substituted, can be isolated by column chromatography and can be held in substance for a number of weeks without appreciable degradation, when in crystallized form and when kept in the dark. It is supposed that the Lewis acid not only activates the peracid, but also coordinates to the oxygen in the formed thiophene S-oxide, thus reducing the electron-density on the sulfur of the thiophene S-oxide, making it less prone to undergo a second oxidation to the thiophene S,S-dioxide.
\n
Scheme 16.
Preparation of thiophene S-oxides 65 by oxidation of thiophenes 64 in the presence of a Lewis acid or a protonic acid.
\n
It has been shown that in a molecule, such as 66 or 67, with two thienyl cores, both can be oxidized to thienyl-S-oxides with m-CPBA, BF3·Et2O CH2Cl2, −20°C) [11, 17] . Under these conditions, the second thiophene unit can compete successfully with a thiophene S-oxide for the oxidant (Figure 4).
\n
Figure 4.
Known bisthienyl-S-oxides 66 and 67.
\n
\n
\n
4. Reactions of thiophene S-oxides
\n
\n
4.1. [4 + 2]-cycloaddition reactions
\n
Even before thiophene S-oxides could be isolated in pure form, it was evident that thiophene S-oxides are good dienes in cycloaddition reactions, as “trapping” by cycloaddition reaction was one of the standard techniques to gauge the presence of thiophene S-oxide intermediates and provided a versatile preparative entry to 7-thiabi-cyclo[2.2.1]heptene S-oxides 68. These in turn could be converted to substituted arenes 71 by either pyrolysis [15], photolysis [51], or PTC-catalyzed oxidative treatment with KMnO4 [15] or electrochemical oxidation [18] or 7-thiabicyclo-[2.2.1]heptenes (70) by reaction of 68 with PBr3 [52]. Reaction of 68 with tributyltin hydride gives cyclic dienes such as 72 [▬X▬X▬ = ▬(CO)N▬Ph(CO)▬]. Base catalyzed cleavage of the sulfoxy bridge of 1,4-dihalo-7-thiabicyclo[2.2.1]heptane S-oxides 68 (R1 = Cl or Br) leads to the generation of diaryl disulfides such as 69 (Scheme 17).
\n
Scheme 17.
7-Thiabicyclo[2.2.1]heptene S-oxides 68 as versatile precursors to arenes.
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With the possibility of isolating the thiophene S-oxides, it became possible to carry out cycloaddition reactions with alkenes that themselves react with m-CPBA. Thiophene S-oxides such as 73 have been found to react equally well with electron-rich alkenes such as enol ethers (74) [53], with electron neutral alkenes such as with cyclopentene (76) [53, 54] and with electron-poor alkenes such as with cyclopentenone or with maleic anhydride [11, 54] (Scheme 18). Also, thiophene S-oxides react with bicyclopropylidene (82) [55] under high pressure (10 kBar, Scheme 19), with allenes [56] (such as 79, Scheme 19), with cyclopropylideneketone [55] (Scheme 20) and with benzyne (90) [56], both formed in-situ (Scheme 21). The reaction of tetrachlorocyclopropene (93) with 3,4-bis-tert-butylthiophene S-oxide (73) led to 6,7-bis-tert-butyl-2,3,4,4-tetrachloro-8-thiabicyclo[3.2.1]octa-2,6-diene 8-oxide (95), resulting from a ring opening of the primary cycloadduct 94 with a concomitant migration of a chloro atom [57] (Scheme 22). The ability of the thiophene S-oxides to undergo cycloadditions with alkenes, regardless of the electron demand of the reaction, has made Houk et al. say that thiophene 1-oxide cycloadditions warrant their classification as click reactions [23].
\n
Scheme 18.
3,4-Bis-tert-butylthiophene S-oxide (73) cycloadding to electron-rich and electron-neutral alkenes.
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Scheme 19.
Thiophene S-oxides cycloadd to allenes and to bicyclopropylidene (82) under high pressure.
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Scheme 20.
One pot Wittig reaction—Diels Alder reaction with thiophene S-oxide 87 as diene.
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Scheme 21.
Cycloaddition of thiophene S-oxide 91 with benzyne (90), prepared in situ.
\n
Scheme 22.
Cycloaddition of thiophene S-oxide (73) with tetrachlorocyclopropene (93).
\n
Thiophene S-oxides are good precursors for the preparation of heavily substituted arenes such as 100 [58] (Scheme 23). Often, tetraarylcyclopentadienones 97 are used to synthesize oligoaryl benzenes by cycloaddition reaction. However, tetraphenylthiophene S-oxide (96) is the more reactive diene when compared to tetraphenylcyclopentadienone (97) as can be seen in the competitive cycloaddition of 96 and 97 with N-phenylmaleimide (98), where at room temperature only tetraphenylthiophene S-oxide undergoes cycloaddition to give 99 (Scheme 23) [58]. 99 can be converted to the heavily substituted phthalimide 100 [58], either by extruding the SO group thermally in diphenyl ether (Scheme 23) or by reaction with KMnO4/PTC.
\n
Scheme 23.
Thiophene S-oxide 96 competes efficiently with tetracyclone 97 for N-phenylmaleimide (98).
\n
Sometimes, tetraphenylthiophene S-oxide (96) and tetraphenylcyclopentadienone (97) give different products in cycloaddition reactions. A typical example is their cycloaddition to benzo[b]thiophene S,S-dioxide (101), where the reaction with 96 leads to the formation of dibenzothiophene S,S-dioxide 102, but with 97 gives dibenzothiophene 104 [59] (Scheme 24). The reason for this difference lies in the tendency of tetracyclines such as 94 to be oxidized to pyrones 102 at higher reaction temperatures, with the S,S-dioxides playing the oxidizing agent [59] (Scheme 24).
\n
Scheme 24.
Comparison of the cycloaddition of tetraphenylthiophene S-oxide 96 and tetracyclone 97 with benzo[b]thiophene S,S-dioxide (101). Tetracyclone 97 gives pyrone 105 as side product [59, 60].
\n
Again, cycloaddition reactions of purified thiophene S-oxides can be used to prepare multifunctionalized arenes such as cyclophanes (Scheme 25) [25]. Nakayama et al. [61] have used thiophene S-oxides to prepare sterically over freighted anthraquinones. Thiemann et al. [62] used halogenated thiophene S-oxides, albeit prepared in-situ to synthesize halogenated anthraquinones, which can easily be transformed further to arylated anthraquinones [63, 64]. The cycloaddition reactions of purified thiophene S-oxides can be combined with other transformations in one pot, such as with Wittig olefination reactions (Scheme 20) [55].
\n
Scheme 25.
Multifunctionalized cyclophanes 108 by cycloaddition of thiophenophane S-oxides 106.
\n
Not all thiophene S-oxides undergo cycloaddition reactions with alkynes or alkenes. In general, appreciable reaction volume is needed to allow for the forming sulfoxy-bridge in the primary cycloadducts and, in some cases, of the subsequent extrusion of SO. Also, when considerable strain is associated with the thiophene S-oxides and/or the cycloadducts, reactions other than cycloadditions can occur. Thus, strained thiophenophane S-oxide 110 does not undergo a cycloaddition with 98, but undergoes a rearrangement leading to oxygen insertion into the ring with concomitant extrusion of sulfur, leading to furanophane 111 (Scheme 26) [25]. Fujihara et al. were able to prepare the thiacalixarene S-oxide 112; again, the thiacalixarene S-oxide did not undergo a cycloaddition reaction with alkyne 113, but rather formed the thiophene-S,C-sulfonium ylide 114 (Scheme 27) [65].
\n
Scheme 26.
[2.2]Metathiophenophane S-oxide 109 does not undergo cycloaddition but rearranges to [2.2]furanophane 111.
\n
Scheme 27.
Thiacalixarene S-oxide 112 reacts with dimethyl acetylenedicarboxylate (113) to the thiacalixarene S,C-ylide 114.
\n
Thiophene S-oxides as cyclic dienes undergo hetero-Diels-Alder reactions, also (Scheme 28). Thus, Nakayama et al. could establish that 3,4-bis-tert-butylthiophene S-oxide 73 reacts with thioaldehydes 115/117 and thioketones 115, generated in-situ to give 2,7-dithiabicyclo[2.2.1]hept-5-ene 7-oxides 116 and 118 [66] (Scheme 28). The cycloadducts are endo-products as ascertained by X-ray crystallography and 1H NMR spectroscopy. Thiobenzophenone could be reacted with good yield; however, here two isomeric products are produced, the major product originating from the syn-π-face while the lesser product from the anti-π-face cycloaddition.
\n
Scheme 28.
Hetero-Diels-Alder reactions of 3,4-bis-tert-butylthiophene S-oxide (73).
\n
Finally, 73 reacts with carbonyl cyanide [121, CO(CN)2], created in-situ by oxidation of tetracyanoethylene oxide (119, TCNO) with thiophene S-oxide 73, in hetero-Diels-Alder fashion to give 122 [67] (Scheme 29).
\n
Scheme 29.
Reaction of 3,4-tert-butylthiophene S-oxide (73) with tetracyanoethylene oxide (119, TCNO) and hetero-Diels Alder reaction to carbonyl cyanide (121).
\n
Nakayama et al. have calculated that the cycloadditions of the thiophene S-oxides are inverse electron demand reactions [53]. All of the above cycloaddition reactions are highly stereoselective, regardless whether the thiophene S-oxide is prepared and used in-situ or an isolated thiophene S-oxide is used. It is known that the thiophene S-oxides invert at the sulfur and inversion barriers have been calculated and measured experimentally for a number of these compounds [32, 68, 69]. Nevertheless, the sulfoxy group in the 7-thiabicyclo[2.2.1]heptene S-oxide systems is configurational stable. All the cycloadducts are endo-products. In the cases where Lewis acids are used at low temperatures, this in itself is not surprising as it is known that low temperatures kinetically controlled cycloadducts are favored. Moreover, it has been stated that Lewis acid catalysis increases the extent of endo-addition in Diels-Alder reactions [70, 71]. The cycloadditions are seen to have syn-π-facial in that the dienophile adds syn to the oxygen. This means that the lone pair of the sulfur is directed towards the side of the newly formed double bond of the cycloadduct. A number of explanations have been given for the π-facial selectivity. Thus, Nakayama et al. rationalized that in the transition state less geometric change of the SO function would be required to reach the syn- rather than the anti-transition state geometry [53]. Also, a destabilizing interaction between the HOMO of the dienophile and the sulfur lone pair was noted in the anti-transition state [72]. The π-facial selectivity has also been explained by the Cieplak effect [73, 74, 75]. This effect was first proposed to account for the directing effect of remote substituents in addition reactions to substituted cyclohexanones. A large number of experimental observations in Diels-Alder reactions of dienophiles with 5-substituted cyclopentadienes have shown that the dienophiles will approach anti to the antiperiplanar σ-bond that is the better donor at the 5-position of the cyclopentadiene [76]. This σ-bond will best stabilize the σ-bonds formed in the transition state. Cycloadditions to thiophene S-monoxides have been predicted to occur anti to the lone electron-pair on sulfur, which is the better hyper-conjugative donor when compared to the oxygen of the sulfoxy-moiety. The lone pair electron orbital at the sulfur will stabilize the vacant σ*-orbitals of the developing incipient σ-bonds better than any orbital associated with the oxygen of the sulfoxy moiety [77] (Figure 5). This would be even more so, when the oxygen of the sulfoxy-unit is complexed by BF3·Et2O.
\n
Figure 5.
Transition state 123 preferred over transition state 124.
\n
Based on DFT computational studies, Houk et al. [23] showed that the ground state geometry of a thiophene S-oxide already resembles the molecule in its syn transition state. This distortion from planarity of the molecule minimizes its potential antiaromaticity which would result from a hyperconjugative effect by an overlap of σ*S〓O with the π-system (see also above/below) [23] (Figure 6).
\n
Figure 6.
Structural feature of thiophene S-oxide 160.
\n
\n
\n
4.2. Further cycloaddition reactions
\n
When heated with 2-methylene-1,3-dimethylimidazoline (125), 3,4-bis(tert-butyl)thiophene S-oxide 73 undergoes a [4π + 4π]-cycloaddition to the head-to-head dimer 126 (Scheme 30) [78]. Oxidation of the two sulfoxy bridges to sulfone 127 with dimethyldioxirane as oxidant is followed by thermally driven extrusions of the SO2 bridges in 127 and gives 1,2,5,6-tetra(tert-butyl)octatetraene 128 [79] (Scheme 30).
\n
Scheme 30.
[4π + 4π]-cycloaddition of thiophene S-oxide (73) to dimer 126.
\n
Thiophene S-oxides react as enes in 1,3-dipolar cycloaddition reactions. Thus, 3,4-bis-tert-butylthiophene S-oxide (73) reacts with pyrroline N-oxide (129) to give cycloadduct 130 (Scheme 31) [80]. Nakayama et al. could show that 73 reacts with nitrile oxides, diazomethane, nitrile imides, nitrones, and azomethine ylides in syn-π-facial fashion [80].
\n
Scheme 31.
[3 + 2]-cycloaddition of thiophene S-oxide (73) with pyrroline N-oxide (129) as 1,3-dipole.
\n
\n
\n
4.3. Additions to thiophene S-oxides and other reactions
\n
1,4-Additions are known for both 3,4-disubstituted and 2,5-disubstituted thiophene S-oxides [81, 82, 83]. Thus, bromine adds cis to both 3,4-bis-tert-butylthiophene S-oxide (73) [81] and 2,5-bis-trimethylsilylthiophene S-oxide (134) [82] to give the 2,5-dibromo-2,5-dihydrothiophene S-oxide derivatives 131 and 135 (Scheme 32). 3,4-Bis-tert-butylthiophene S,S-dioxide (132) undergoes cis-1,4-bromination, too [81] (Scheme 32). Also, alcohols and mercaptans have been submitted successfully to 1,4-additions with 3,4-bis-tert-butyl thiophene S-oxide (73) (Scheme 33) [83]. Interestingly, disulfur dichloride (S2Cl2) could be added to thiophene S-oxide 73, leading to the rapid formation of adduct 137 (Scheme 34) [84]. 137, however, is not stable and transforms into 138. 138 can be obtained with a 98% yield, when 137 is treated with aq. NaHCO3 (Scheme 34) [84].
\n
Scheme 32.
Bromination of thiophene S-oxides 73 and 134 and thiophene S,S-dioxide 132.
\n
Scheme 33.
Addition of methylthiolate to thiophene S-oxide (73).
\n
Scheme 34.
Addition of disulfur dichloride (S2Cl2) to thiophene S-oxide 73.
\n
The sulfoxy group in thiophene S-oxide can be transformed into a sulfilimine or a sulfoximine moiety [85, 86, 87]. When thiophene S-oxide 73 is reacted with trifluoroacetic acid anhydride or triflic anhydride at −78°C, a mixture of sulfonium salt 139 and sulfurane 140 forms, which can be reacted with p-toluenesulfonamide (141) to provide, as the reaction mixture warms to room temperature, sulfilimine 142 (Scheme 35) [85, 86]. Sulfoximine 145 could be prepared by action of N-[(p-tolylsulfonyl)imino]phenyliodinane (TsN〓IPh, 144) on 2,4-bis-tert-butylthiophene S-oxide (143) in the presence of Cu(CH3CN)4PF6 as catalyst. Further reaction of 145 with H2SO4 leads to N-unsubstituted sulfoximine 146 (Scheme 36) [86].
\n
Scheme 35.
Preparation of thiophene S-imide 142 from thiophene S-oxide 73.
\n
Scheme 36.
Thiophene sulfoximines 145 and 146 from thiophene S-oxide 143.
\n
\n
\n
4.4. Photochemistry of thiophene S-oxides
\n
The photochemical deoxygenation of dibenzothiophene S-oxides has been studied for quite some time [88, 89, 90, 91] and has been found to proceed via the release of ground state atomic oxygen [O(3P)] upon photoirradiation (Scheme 37). Thiophene S-oxides deoxygenate photochemically as well. Nevertheless, the photochemistry of thiophene S-oxides is intrinsically more complex than that of dibenzothiophene S-oxides, often providing a mixture of products, depending on the substitution pattern of the photoirradiated thiophene S-oxide. The photolysis of 2,5-bis(trimethylsilyl)thiophene S-oxide (134) leads exclusively to deoxygenation to produce 2,5-trimethylsilylthiophene (149) (Scheme 38). Otherwise, in those cases, where the thiophene S-oxide does not exhibit a CH3 substituent on the ring system, furans are often the main products along with (deoxygenated) thiophenes (Scheme 39). This has been noted with phenyl-substituted (96, 160) and tert-butyl substituted thiophene S-oxides (73, 143, 153) as well as with 3,4-dibenzylthiophene S-oxide (158) (Scheme 40) [92, 93, 94, 95]. Different mechanisms have been forwarded for this photochemical formation of furans. A viable mechanism involves a cyclic oxathiin, where the first step within the photochemical reaction is initiated by the homolytic ring cleavage α to the sulfoxy group [92, 93, 94]. A rearrangement of thiophene S-oxides to produce furans can also proceed thermally as found by Thiemann et al. [18] in the transformation of thiophenophane S-oxide 110 to furanophane 111 (Scheme 26) and by Mansuy, Dansette et al. in their oxidation of 2,5-diphenylthiophene (162) with H2O2/CF3CO2H to 2,5-diphenylthiophene S-oxide (163), where an appreciable amount of furan 164 was formed as side-product [46] (Scheme 41). In the case of methyl substituted thiophene S-oxides, hydroxyl-alkylthiophenes such as 166 and follow-up products such as ether 167 have been isolated as photoproducts [96] (Scheme 42).
\n
Scheme 37.
Photodeoxygenation of dibenzothiophene S-oxide (147).
\n
Scheme 38.
Photolysis of 2,5-bis(trimethylsilyl)thiophene S-oxide (134).
\n
Scheme 39.
Photolysis of tetraphenylthiophene S-oxide (96).
\n
Scheme 40.
Photolysis of 2,4-bis(tert-butyl)-, 2,5-bis(tert-butyl), 3,4-bis(tert-butyl), 3,4-dibenzyl-, and 2,5-diphenylthiophene S-oxide (143, 153, 73, 158, and 160).
\n
Scheme 41.
Formation of furan 163 in the oxidation of 2,5-diphenylthiophene (162).
\n
Scheme 42.
Photolysis of 3,4-dibenzyl-2,5-dimethylthiophene S-oxide (165).
\n
\n
\n
4.5. Electrochemistry of thiophene S-oxides
\n
Thiophene S-oxides such as 164 and 167 show well-defined, chemically irreversible CV reduction waves, where two reduction processes seem to compete. In the presence of a proton donor, the reduction waves experience a significant shift to more positive potentials, although the reduction potential is still dependent on the substitution pattern of the thiophene S-oxides [96]. In the presence of a proton donor such as benzoic acid at higher concentrations, the reduction of a thiophene S-oxide such as of 167 becomes a straightforward two proton—two electron reduction process to the corresponding thiophene [96]. Bulk electrolysis of thiophene S-oxides in presence of 10-fold excess of benzoic acid has been carried out and have led to the corresponding thiophenes in up to 90% isolated yield (Scheme 43) [96]. Also, thiophene S-oxides show oxidative electrochemistry at platinum in MeCN/Bu4NPF6 [97]. The electrochemical oxidation of tetraphenylthiophene S-oxide under the above conditions leads mainly to the formation of diphenylacylstilbene [98]. Here, more effort needs to be invested to identify the electro-oxidative transformations of other thiophene S-oxides.
\n
Scheme 43.
Electrochemical reduction of 3,4-dibromo-2,5-dimethylthiophene S-oxide (167) in the presence of 10 eq. benzoic acid.
\n
\n
\n
4.6. Structural studies on thiophene S-oxides
\n
In 1990, Rauchfuss et al. published an X-ray crystal structure of the tetramethylthiophene S-oxide rhodium complex 56 [34]. The first X-ray single crystal structure determination of a non-liganded thiophene S-oxide was carried out by Meier-Brocks and Weiss on tetraphenylthiophene S-oxide. The crystal, however, showed some disorder, and only limited information could be gleaned from it [39]. In 1995, Mansuy et al. carried out an X-ray crystal structural analysis of 2,5-diphenylthiophene S-oxide (160) [46, 47], where the structure of 160 was compared to 2,5-diphenylthiophene (162) and 2,5-diphenylthiophene S,S-dioxide (169). The S▬O bond in the thiophene S-oxide was found with 1.484(3) Å to be appreciably longer than those of the thiophene S,S-dioxide with 1.418(5) Å and 1.427(5) Å, respectively [47]. The ring system of the thiophene S,S-dioxide 169 was found to be absolutely planar, while thiophene S-oxide 160 was found to be puckered, with the sulfur lying outside the plane constructed by the four ring carbons by 0.278 Å, and the sulfoxy oxygen lying outside of the plane on the side opposite to sulfur, located by 0.746 Å away from the plane. Previously, this non-planarity of thiophene S-oxides had been predicted by MNDO [99] and ab-initio calculations [100] of the parent thiophene S-oxide itself and dibenzothiophene S-oxide. A more pronounced alteration between double and single C▬C bond was found in thiophene S-oxide 160 in comparison to diphenylthiophene [47]. In probing the aromaticity of thiophene S-oxide 160, it can be seen that apart from its non-planarity, it exhibits relatively large bond order alternations [C(2)▬C(3) 2.11; C(3)▬C(4) 1.23, C(2)/C(5)▬S 1.11; for comparison, the bond orders in 162: C(2)▬C(3) 1.94; C(3)▬C(4) 1.46; C(2)/C(5) 1.53]. The corresponding 2,5-diphenylthiophene S,S-dioxide, though features even larger bond alternations than 160 [47]. An approach for an assessment of aromaticity is the A index as defined by Julg and François [101], which evaluates aromaticity in respect to bond alternation and bond delocalization in ring systems. Here, benzene as the aromatic system par excellence, has an A index of 1, the thiophene system in 2,5-diphenylthiophene has an A index of 0.99, the 5-membered ring system in 2,5-diphenylthiophene S-oxide’s A index is calculated at 0.79, and the parent thiophene S-oxide A index lies at 0.69 ([47], see also [102]).
\n
Subsequently, further X-ray crystal structure analyses were carried out on thiophene S-oxide, such as on 2,5-bis(diphenylmethylsilyl)thiophene S-oxide [45], 3,4-bis-tert-butylthiophene S-oxide (73) [43], (1,1,7,7-tetraethyl-3,3,5,5-tetramethyl-s-hydrindacen-4-yl)thiophene S-oxide [68], 1,3-bis(thien-2yl)-4,5,6,7-tetrahydrobenzo[c]thiophene S-oxide [40], and the sexithiophene (170) (Figure 7), where two of the thienyl units were oxidized to sulfoxides [103]. As the thiophene S-oxides are not planar, they invert at the sulfur with different substituents at the C2/C5 positions leading to different barriers of inversion, which have in part been determined experimentally [32, 68, 69]. Structural features of thiophene S-oxides and thiophene S,S-dioxides have been reviewed before [104].
\n
Figure 7.
Oligothiophene S-oxide 170.
\n
\n
\n
4.7. Oligomers and polymers incorporating thiophene S-oxide units
\n
Oligothiophenes and polythiophenes are being studied as advanced materials with interesting electronic and nonlinear optical properties [105] with applications in photovoltaic cells [106] and field effect transistors (FETs) [107], among others. It has been noted that oxidation of thienyl-units in oligothiophenes and polythiophenes leads to a lowering of energy gaps, to greater electron affinities, and to greater ionization energies [103, 108, 109]. The introduction of thienyl-S,S-dioxides into oligothiophenes often leads to solubility problems of the materials and often leads to a noticeable increase of oxidation potentials. Therefore, there has been a recent interest in incorporating thienyl S-oxide units in oligo- and polythiophenes with the aim of greater solubility and smaller oxidation potentials and narrower energy gaps with electron-affinities similar to thienyl S,S-dioxides [103].
\n
A number of synthetic approaches exist towards the preparation of oligothiophenes with thienyl S-oxide units. Oxidation of a pre-prepared oligo- or polythiophene is more difficult to achieve and leads to modest yield [110]. However, two strategies can be seen as promising. One is the transformation of polyarylene-alkynes 171 via oligozirconacyclopentadienes 172 to polythiophene S-oxides 173, where the zirconacyclopentadienes are reacted with SO2 [41] (Scheme 44). The other takes advantage of the fact that certain thiophene S-oxides such as 2-bromo-3,4-diphenyl-thiophene S-oxide (175) are stable enough to be subjected to C▬C cross-coupling reactions and subsequent halogenation reactions with N-bromosuccinimide (NBS), leading to sequences as shown in Scheme 45 [103]. Already, an FET has been synthesized with a thienyl-thienyl S-oxide polymer [103]. Also, larger π-conjugated ring systems with a thienyl S-oxide unit such as 179 have attracted some attention because of their electronic and optical properties (Figure 8) [111]. As a drawback, it may be noted that thienyl S-oxides in oligomers and polymers would not be stable towards UV radiation as opposed to thienyl S,S-dioxides [112, 113].
\n
Scheme 44.
Preparation with oligomer 173 via zirconacyclopentadiene 172.
\n
Scheme 45.
Preparation of thienyl S-oxide containing oligomers 170 and 178 by Pd(0) Suzuki and Stille cross-coupling reactions.
4.8. Thiophene S-oxides as metabolites in the enzymatic oxidation of thiophenes
\n
Thiophenes have been known to have toxic effects [114, 115]. The understanding of the mechanism leading to the toxicity of thiophenes is of importance, as a number of drugs such as tienilic acid (180), ticlopidine (182), methapyrilene (183), thenalidine (184), tenoxicam (185), cephaloridine (186), suprofen (187), and clopidogrel (188) carry thienyl units, where some of the drugs have been taken off the market (Figure 9). Already in 1990, it was shown that hepatic cytochrome P450 mediated oxidation of the thienyl-containing tienilic acid (180) led to electrophilic metabolites that bind to hepatic proteins [116, 117]. Oxidative metabolism of thiophenes in rats involves thiophene S-oxides [118, 119, 120]. It has been found [119, 121] that rats administered with thiophene (1) in corn oil showed dihydrothiophene S-oxide 191 in their urine as a major metabolite [119] (Scheme 46). This metabolite was assumed to stem from the addition of glutathione (189) to a reactive intermediate thiophene S-oxide 3 (Scheme 46). Previously, it had been shown that rat liver microsomal cytochrome P450 oxidizes 3-aroylthiophene 181, a regioisomer of tienilic acid (180), to aroylthiophene S-oxide 192, which in the presence of mercaptoethanol (193) transformed into dihydrothiophene S-oxide 194 [121] (Scheme 47). Also, 181 was oxidized by clofibrate induced rat liver microsomes to S-oxide 191, which was then trapped as a Diels Alder product with maleimides, for example as 195 [120] (Scheme 48).
\n
Figure 9.
Thiophene-containing pharmaceuticals.
\n
Scheme 46.
Cytochrome P450 mediated transformation of thiophene 1 to adduct 191.
\n
Scheme 47.
Transformation of tienilic acid regioisomer 181 to thiophene S-oxide and its addition of mercaptoethanol (193).
\n
Scheme 48.
Cycloaddition of the thiophene S-oxide derivative of 181 to maleimide.
\n
The oxidation of 2-(4-chlorobenzoyl)thiophene (196), a molecule in structure close to tienilic acid, by H2O2 in the presence of trifluoroacetic acid (TFA) and by m-CPBA, BF3·Et2O, both in CH2Cl2, gives sesquioxides 198–200 that clearly indicate that a thiophene S-oxide structure 197 is formed as an intermediate [122] (Scheme 49). Nevertheless, the oxidation of thiophene (1) itself with H2O2 in the presence of TFA produces apart from sesquioxides 6–8 thiophen-2-one (thiolactone 202). Thiophen-2-one (202) most likely is produced through thiophene-epoxide (201) [23] (Scheme 50). Thiophen-2-one (202) is in equilibrium with 2-hydroxythiophene (202). There is one report of a Pummerer-like rearrangement reaction that leads from the purified and isolated thiophene S-oxide 134 to thiophen-2-one (thiolactone 202) [123] (Scheme 51). Still, the current understanding is that the thiophene S-oxide intermediates formed in vivo do not lead to a 2-hydroxythiophene (203) [124] (Scheme 52), so that two separate mechanisms may exist for the cytochrome P450 2C9 (CYP2C9) mediated oxidation of thiophenes. In this regard, Dansette et al. [119] showed that CYP450s may catalyze both the reaction of thiophenes to thiophene S-oxide and to thiophene epoxides [125].
\n
Scheme 49.
Formation of sequioxides 198–200 by dimerization of thiophene S-oxide 197.
\n
Scheme 50.
Reaction of thiophene (1) leads via thiophene S-oxide (3) to sesquioxides 7–9 and in a separate pathway via thiophene epoxide 201 to thiolactone 202 and thus to 2-hydroxythiophene (203).
\n
Scheme 51.
Pummerer reaction of thiophene S-oxide 134 to thiolactone 202.
\n
Scheme 52.
Cytochrome P450 mediated oxidation of thiophene may lead to two pathways, one through thiophene S-oxide 3, the other through thiophene epoxide 201.
\n
Also, the investigation of the metabolism of other thienyl-containing pharmaceuticals show that potentially both mechanisms, epoxidation of the thiophene-unit and oxidation of the thiophene-unit to thiophene S-oxide, operate concurrently. As to the thiophene S-oxide pathway, Shimizu et al. in their investigation of metabolites ticlopidine (182) in rats found both the glutathione conjugate of ticlopidine S-oxide 205 and the dimeric ticlopidine S-oxide cycloadduct 206 (Figure 10) [126, 127]. The structures could be identified by mass spectrometry, and 1H and 13C NMR spectrometry. Medower et al. have noted that cytochrome P450 mediated oxidation of cancer drug OSI-930 (207) leads to GSH conjugate 209, derived from OSI-930 S-oxide (208), as recognized by mass spectrometry (Scheme 53) [128].
\n
Figure 10.
Metabolites of ticlopidine that derive from a ticlopidine S-oxide intermediate.
\n
Scheme 53.
In vivo oxidation of anticancer drug OSI-930 (207) to OSI-930 sulfoxide (208) and addition of glutathione (GSH) to provide identified metabolite 209.
\n
Lastly, both possible metabolic pathways of thiophenes, via thiophene S-oxides and via thiophene epoxides, have been examined as to their energy profiles using density functional theory [129]. It was found that the formation of the thiophene epoxide (−23.24 kcal/mol) is more exothermic than the formation of the thiophene S-oxide (−8.08 kcal/mol) [129]. Also, the formation of thiophene epoxide seems kinetically favored [129]. Both possible metabolites, thiophene S-oxide and thiophene epoxide, are highly electrophilic, leading to bond formation with nucleophiles such as with amino acids, leading to a mechanism-based inactivation (MBI) of cytochrome P450.
\n
\n
\n
\n
5. Conclusion
\n
Since the first unverified isolation of a thiophene S-oxide a little more than 50 years ago, research on thiophene S-oxides has reached a milestone. Due to mainly two synthetic routes, the controlled oxidation of thiophenes in presence of a Lewis- or proton acid and the reaction of zirconacyclopentadienes with thionyl chloride, a number of thiophene S-oxides have now become readily accessible. Thiophene S-oxides are noted to be reactive dienes in Diels-Alder type cycloadditions, where they react equally well with electron-poor and electron-rich dienophiles. Thiophene S-oxides can be stabilized by sterically exacting substituents. Then, they exhibit sufficient stability to be submitted to Pd(0)-catalyzed cross-coupling reactions without deoxygenation.
\n
This leads to the possibility of preparing aryl-oligomers with thiophene-S-oxide subunits. By comparing oligothiophenes and oligomers with thiophene S,S-dioxide subunits, oligomers with thiophene S-oxide subunits exhibit smaller oxidation potentials and narrower energy gaps with electron-affinities greater than oligothiophenes and similar to thiophene S,S-dioxides. Nevertheless, thiophene S-oxides are not stable photochemically, but deoxygenate to the corresponding thiophenes or transform to furans by photochemical rearrangement.
\n
Thiophene S-oxides have been found to act as intermediates in the cytochrome P540 mediated, oxidative metabolism of thiophene-containing compounds, including a number of important thiophene containing pharmaceuticals. Addition of nucleophiles in vivo leads to mechanism based inhibition (MBI) and to toxic side effects of the thiophenes, including nephrotoxicity.
\n
\n\n',keywords:"thiophenes, selective oxidation, cycloaddition, functionalized arenes, drug metabolites",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/62502.pdf",chapterXML:"https://mts.intechopen.com/source/xml/62502.xml",downloadPdfUrl:"/chapter/pdf-download/62502",previewPdfUrl:"/chapter/pdf-preview/62502",totalDownloads:684,totalViews:250,totalCrossrefCites:0,dateSubmitted:"January 12th 2018",dateReviewed:"May 23rd 2018",datePrePublished:"November 5th 2018",datePublished:"February 20th 2019",dateFinished:"July 6th 2018",readingETA:"0",abstract:"Thiophene S-oxides constitute a class of molecules that have been studied in more detail only recently. Their existence as intermediates in the peracid mediated oxidation of thiophenes to thiophene S,S-dioxides, however, has been known over some time. Over the last 20 years, a larger number of thiophene S-oxides have been prepared and isolated in pure form. Thiophene S-oxides have been found to be good dienes in [4 + 2]-cycloaddition reactions, where they react with electron-poor, electron-neutral and electron-rich dienophiles with high syn π-facial stereoselectivity. Thiophene S-oxides have been found to be metabolites of thienyl-containing pharmaceuticals such as the anti-platelet drugs ticlopidine and clopidogrel. The chapter gives an overview of the preparation and reactivity of this class of compounds.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/62502",risUrl:"/chapter/ris/62502",signatures:"Thies Thiemann",book:{id:"6797",title:"Chalcogen Chemistry",subtitle:null,fullTitle:"Chalcogen Chemistry",slug:"chalcogen-chemistry",publishedDate:"February 20th 2019",bookSignature:"Peter Papoh Ndibewu",coverURL:"https://cdn.intechopen.com/books/images_new/6797.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"87629",title:"Prof.",name:"Peter",middleName:"Papoh",surname:"Ndibewu",slug:"peter-ndibewu",fullName:"Peter Ndibewu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"199012",title:"Prof.",name:"Thies",middleName:null,surname:"Thiemann",fullName:"Thies Thiemann",slug:"thies-thiemann",email:"thiesthiemann@medjchem.com",position:null,institution:{name:"United Arab Emirates University",institutionURL:null,country:{name:"United Arab Emirates"}}}],sections:[{id:"sec_1",title:"1. Early history of oxidation reactions of thiophenes: cycloaddition reactions of thiophene S-oxides prepared in situ in absence of Lewis acids",level:"1"},{id:"sec_2",title:"2. Cycloaddition reactions of thiophene S-oxide prepared in situ in the presence of Lewis acids: thiophene S-oxides are isolated",level:"1"},{id:"sec_3",title:"3. Preparation and isolation of pure thiophene S-oxides",level:"1"},{id:"sec_4",title:"4. Reactions of thiophene S-oxides",level:"1"},{id:"sec_4_2",title:"4.1. [4 + 2]-cycloaddition reactions",level:"2"},{id:"sec_5_2",title:"4.2. Further cycloaddition reactions",level:"2"},{id:"sec_6_2",title:"4.3. Additions to thiophene S-oxides and other reactions",level:"2"},{id:"sec_7_2",title:"4.4. Photochemistry of thiophene S-oxides",level:"2"},{id:"sec_8_2",title:"4.5. Electrochemistry of thiophene S-oxides",level:"2"},{id:"sec_9_2",title:"4.6. Structural studies on thiophene S-oxides",level:"2"},{id:"sec_10_2",title:"4.7. Oligomers and polymers incorporating thiophene S-oxide units",level:"2"},{id:"sec_11_2",title:"4.8. Thiophene S-oxides as metabolites in the enzymatic oxidation of thiophenes",level:"2"},{id:"sec_13",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Lanfry M. Sur les oxythiophènes. Comptes Rendus. 1911;153:73-76\n'},{id:"B2",body:'Lanfry M. ur les oxy-b-méthylthiophènes. Comptes Rendus. 1911;153:821-822\n'},{id:"B3",body:'Bailey WJ, Cummins EW. Cyclic dienes. III. Synthesis of thiophene 1-dioxide. Journal of the American Chemical Society. 1954;76:1932-1936\n'},{id:"B4",body:'Bailey WJ, Cummins EW. Cyclic dienes. IV. The dimerization of thiophene 1-dioxide. Journal of the American Chemical Society. 1954;76:1936-1940\n'},{id:"B5",body:'Nagasawa H, Sugihara Y, Ishii A, Nakayama J. Thiophene 1,1-dioxide: Synthesis, isolation, and properties. Bulletin of the Chemical Society of Japan. 1999;72:1919-1926\n'},{id:"B6",body:'Benders PH, Reinhoudt DN, Trompenaars WP. 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Journal of Photochemistry and Photobiology A. 2008;198:45-51\n'},{id:"B92",body:'Arima K, Ohira D, Watanabe M, Miura A, Mataka S, Thiemann T, Iniesta J, Walton D. The photochemistry of thiophene S-oxides. Photochemical & Photobiological Sciences. 2005;4:808-816\n'},{id:"B93",body:'Heying MJ, Nag M, Jenks WS. Photochemistry of thiophene S-oxide derivatives. Journal of Physical Organic Chemistry. 2008;21:915-924\n'},{id:"B94",body:'Stoffregen SA, Lee SY, Dickerson P, Jenks WS. Computational investigation of the photochemical deoxygenation of thiophene-S-oxide and selenophene-Se-oxide. Photochemical & Photobiological Sciences. 2014;13:431-438\n'},{id:"B95",body:'Nakayama J, Hiraiwa S, Fujihara T. Photolysis and photo-oxidation of 3,4-di-tert-butylthiophene 1-oxide. Journal of Sulfur Chemistry. 2008;29:243-250\n'},{id:"B96",body:'Thiemann T, Ohira D, Arima K, Sawada T, Mataka S, Marken F, Compton RG, Bull SD, Davies SG. Photochemical and electrochemical behavior of thiophene S-oxides. Journal of Physical Organic Chemistry. 2000;13:648-653\n'},{id:"B97",body:'Valcarel JI, Walton DJ, Fujii H, Thiemann T, Tanaka Y, Mataka S, Mason TJ, Lorimer JP. The sonoelectrooxidation of thiophene S-oxides. Ultrasonics Sonochemistry. 2004;11:227-232\n'},{id:"B98",body:'Iniesta J, Alcock H, Walton DJ, Watanabe M, Mataka S, Thiemann T. Electrochemical oxidation of tetracyclones and tetraphenylthiophene S-oxide. Electrochimica Acta. 2006;51:5682-5690\n'},{id:"B99",body:'Hashmall JA, Horak V, Khoo LE, Quicksall CO, Sun MK. Molecular structure of selected S-methylthiophenium tetrafluoroborates and dibenzothiophene S-oxide. Journal of the American Chemical Society. 1981;103:289-295\n'},{id:"B100",body:'Rozas I. Comparative study of aromaticity in five-membered rings containing S, SO, and SO2 groups. Journal of Physical Organic Chemistry. 1992;5:74-82\n'},{id:"B101",body:'Julg A, François P. 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Journal of Chemical Research. 2003;27(S):60-61; 2003;27(M):248-264\n'},{id:"B114",body:'McMurty RJ, Mitchell JR. Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes including furosemide and cephaloridine. Toxicology and Applied Pharmacology. 1977;42:285-300\n'},{id:"B115",body:'Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, Leroux JP, Homberg JC. Human anti-endoplasmatic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proceedings of the National Academy of Sciences of the United States of America. 1987;84:551-555\n'},{id:"B116",body:'Dansette PM, Amar C, Smith C, Pons C, Mansuy D. Oxidative activation of the thiophene ring by hepatic enzymes. Hydroxylation and formation of electrophilic metabolites during metabolism of tienilic acid and its isomer by rat liver microsomes. 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The Pummerer-like reaction of 2,5-bis(trimethylsilyl)thiophene S-oxide with trifluoroacetic anhydride: Intermediary formation of sulfurane. Heteroatom Chemistry. 2001;15:444-450\n'},{id:"B124",body:'Rademacher PM, Woods CM, Huang QB, Szklarz GD, Nelson SD. Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9. Chemical Research in Toxicology. 2012;25:895-903\n'},{id:"B125",body:'Dansette PM, Bertho G, Mansuy D. First evidence that cytochrome P450 may catalyze both S-oxidation and epoxidation of thiophene derivatives. Biochemical and Biophysical Research Communications. 2005;338:450-455\n'},{id:"B126",body:'Shimizu S, Atsumi R, Nakazawa T, Fujimaki Y, Sudo K, Okazaki O. Metabolism of ticlopidine in rats: Identification of the main biliary metabolite as a glutathione conjugate of ticlopidine S-oxide. Drug Metabolism and Disposition. 2009;37:1904-1915\n'},{id:"B127",body:'Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D. Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry. 2001;40:12112-12122\n'},{id:"B128",body:'Medower C, Wen L, Johnson WW. Cytochrome P450 oxidation of the thiophene-containing anticancer drug 3-[(quinolin-4-ylmethyl)-amino]-thiophene-2-carboxylic acid (4-trifluoromethoxyphenyl)amide to an electrophilic intermediate. Chemical Research in Toxicology. 2008;21:1570-1577\n'},{id:"B129",body:'Jaladanski CK, Taxak N, Varikoti RA, Bharatam PV. Toxicity originating from thiophene containing drugs: Exploring the mechanism using quantum chemical methods. Chemical Research in Toxicology. 2015;28:2364-2376\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Thies Thiemann",address:"thies@uaeu.ac.ae",affiliation:'
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Drawing from our recent work using a co-culture system composed of neurons growing in differential contact with astroglia, we discuss findings that suggest: 1) growth of dendrites, and addition of synapses, can be independent; further, while astroglia promote synapse formation, they inhibit dendritic growth; 2) astroglia mediate dendrite growth through both paracrine, and contact-dependent mechanisms; and 3) astroglia appear to impose pattern by constraining the growth of dendrites within their zones of influence.",signatures:"Christopher S. Wallace and Ginger S. 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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Indexing and listing across major repositories, see details ...
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Currently strongest OA platform with over 150 million downloads
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