**4. Quality of life**

With disease progression, patients with CP report for impaired overall quality of life. Many studies are conducted to investigate the contributing factors, leading to low QoL. Pain significantly correlates with overall health status, physical and mental subscales. Researchers emphasize the role of severity in contrast to pain frequency and pathophysiology. A large study of Machiado et al., including 1024 CP patients, highlights constant pain as well as inability due to pain, smoking status and concomitant co-morbidities to worsen significantly QoL with negative influence on both physical and mental domains, leading to worsened social and family status and health resource utilization. Other assumed factors, which importance differs among the literature data, are disease duration, young age, women, tobacco and alcohol intake, underweight, pancreatic structural changes DM, PEI, prior endoscopic or surgical treatments. Psychologically conditioned disturbances

(depression, anxiety etc.) are linked most often to alcohol abuse and might lead to pain manifestation and impaired QoL. A study, which enrolled non-alcoholic CP patients, significant depressive syndromes were associated with poor QoL. By the newest concepts, the quality of life assessment is an essential part of the monitoring and the outcome in patients with CP. The European Organization for Research and Treatment of Cancer (EORTC QLQ ) has developed a quality of life questionnaire, containing 30 questions (EORTC QLQ-C30), including an additional question about steatorrhea. The questionnaire correlates with body weight gain and a reduced number of daily defecations related to malnutrition and maldigestion. The quality of life improved after adequate dosing in both newly diagnosed and patients receiving suboptimal PERT. Later, an additional panel of 26 questions concerning pancreatic cancer patients (PAN26) was developed. In the United European Gastroenterology evidence based guidelines for the diagnosis and therapy of CP (HaPanEU), quality of life including pain should be assessed through validated questionnaires (SF-12, SF-36, EORTC QLQ C-30, GIQLI). However, effort should be point at improvement of variable factors as psychological status, tobacco, alcohol consumption and nutritional deficiencies in respect to improve QoL and further to delay disease progression, using therapeutic education and physical rehabilitation, behavioral support and medication [6, 99, 184–190].


**4. Conclusion and future perspective**

The research projects presented in this chapter and chapter 8 cover autologous stem cells, intelligent scaffolds, and various cell signaling pathways with regard to tissue engineering and regenerative medicine, from basic principles to clinical applications. Future research should further clarify the importance of functions and mutual relationships of this triad on various levels. In addition to the elements of this triad, efficient tissue regeneration and maintenance of the regenerated tissue require sufficient blood supply and mechanical stress, respectively (Figure 7). These additional elements have been also approached in our ongoing research projects; all combined will produce dramatic advances in our ability to regenerate bony tissues, multilaterally improve the quality of life for all, and provide brighter future perspectives in the field of tissue engineering and regenerative medicine.

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[4] Ito K, Yamada Y, Naiki T, Usami K, Mizuno H, Okada K, Narita Y, Aoki M, Kondo T, Mizuno D, Mase J, Nishiguchi H, Kagami H, Kinoshita K, Hibi H, Nagasaka T, Ueda M. Bone. In: Applied Tissue Engineering, Ueda M., (Ed.), pp.21–45, Rijeka: InTech;

[5] Katagiri W, Yamada Y, Nakamura S, Ito K, Hara K, Hibi H, Ueda M. Regulation of the Wnt signaling pathways during cell culture of human mesenchymal stem cells

[6] Okamoto Y, Tateishi H, Kinoshita K, Tsuchiya S, Hibi H, Ueda M. An experimental study of bone healing around the titanium screw implants in ovariectomized rats: Enhancement of bone healing by bone marrow stromal cells transplantation. Implant

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[8] Hibi H, Ueda M. Supraperiosteal transport distraction osteogenesis for reconstruct‐ ing a segmental defect of the mandible. Journal of Oral and Maxillofacial Surgery

[9] Kinoshita K, Hibi H, Yamada Y, Ueda M. Promoted new bone formation in maxillary distraction osteogenesis using a tissue‐engineered osteogenic material. Journal of

[10] Jensen O. T, Laster Z, Hibi H, Yamada Y, Ueda M. Alveolar distraction osteogenesis and tissue engineering. In: Tissue Engineering: Applications in oral and maxillofacial surgery and periodontics, 2nd edition, Lynch S. E, Marx R. E, Nevins M, Wisner‐

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**Figure 7.** Elements required for efficient tissue regeneration and maintenance of the regenerated tissue


**5. Conclusions**

Cocrystallization led to altered crystallographic (supramolecular) features as compared to the parent components owing to the creation of a new multi-component crystal phase, which resulted to improved tabletability. This work assessed particle (crystal) and bulk level deformation behaviour of the molecular solids containing no active slip plane (i.e., MAL), a single active slip plane (i.e., RIV-MAL Co) and two slip planes of different surface topologies (RIV).

The BA in RIV was attributed to different surface topologies (flat and corrugated) of two active slip plane systems and higher elastic recovery of RIV crystals. The higher true density and the higher degree of intermolecular interactions due to the 3D interlocked structure offered reasonably good BS to MAL compacts. Concurrently, the strong intermolecular interactions resisted the densification under applied compaction pressure and hence resulted in a decrease in BA. The API and coformer displayed poor particle and bulk deformation; however, RIV-MAL compacts exhibited higher BA and greater BS. The cocrystal with highest BA and BS demonstrated significantly highest tabletability amongst the three samples. The increasing BA was attributed to the presence of flat-layered slip plane and the higher inter-planar distance, while the higher BS was ascribed to the increased degree of intermolecular interactions. During tabletability evaluation of molecular organic solids, plasticity signifies the role of the only BA. The present work stresses the necessity of understanding the role of BS as well.

The particle level deformation parameter H/E was found to inversely correlate with bulk level deformation parameter σ0, which has been commonly used to indicate BS. We suggest the utility of this correlation for estimation of bulk deformation behaviour based on the crystal deformation behaviour studied using nanoindentation experimentation. The predictability of this relationship needs to be further verified by studying more organic molecular solids.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/6/546/s1. Table S1. Slip plane identification by different methods. Figure S1. Heckel plot fitted for estimating Py value of for MAL. Figure S2. Heckel plot fitted for estimating Py value of RIV. Figure S3. Heckel plot fitted for estimating Py value of RIV-MAL Co.

**Author Contributions:** Conceptualization, and Methodology, D.P.K.; Formal Analysis, D.P.K. and V.P.; Investigation, D.P.K., V.P., A.K. and N.K.; Project administration and Supervision, A.K.B.; Writing—original draft, D.P.K. and A.K.B. All authors have read and agreed to the published version of the manuscript.

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

**Acknowledgments:** The authors acknowledge the technical support from Ram Naresh Yadav of IIT, Ropar (India) for nanoindentation experimentation and Jayprakash A. Yadav for CTC profiling. Kailas S. Khomane is deeply acknowledged for the insightful discussion. We are also thankful to MSN Laboratories, India, for providing gift sample of rivaroxaban API. Further, Dnyaneshwar acknowledges the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for Research Fellowship.

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


**7. Necropsy**

A definitive diagnosis of TP can be provided via post-mortem examination and this is carried out in most academic studies to allow correlation to other clinical findings [6, 11]. On necropsy, a malodourous, fibrinous to purulent pericarditis with extensive adhesions is found in TP cases. Other changes are also frequently found within the thorax and abdomen; these commonly include a congested liver, hepatomegaly, liver abscessation and peritoneal effusion [6, 11]. Sometimes the foreign object is located penetrating through the reticulum, diaphragm and pericardium, but not always [4, 11].


**2.1 Beetroot**

Beetroot (*B. vulgaris* subsp. *vulgaris* L.) (Family: Chenopodiaceae) also known as red beetroot has fleshy root that is commonly consumed in form of supplemental juice, powder, bread, gel, oven-dried, pickled, pureed or jam-processed across different food cultures. Its bioactive phytochemicals include phenolics and carotenoids, and betalains hydrosoluble nitrogen containing pigments (e.g., betacyanin that are red-violet and betaxanthin that are yellow-orange) [21]. Betalains form 70–100% of the total phenolics and have antioxidant and anti-inflammatory properties and anticarcinogenic potential [22]. Antiviral and antimicrobial effects of betalain pigments have also been reported [23]. Other antioxidant compounds include rutin, epicatechin, and caffeic acid. The sugar comprises mainly of sucrose (91.6%) [24], with a small and relatively similar proportion of glucose and fructose [25]. Red beetroot also contains dietary fiber, minerals (e.g., potassium, sodium, iron, copper, magnesium, calcium, phosphorus, and zinc), and vitamins (e.g., retinol, folate, ascorbic acid, and B-complex [26]. Moreover, beetroot contains a substantial amount of both nonessential and essential amino acids.

#### **2.2 Cassava**

Cassava (*M. esculenta* Crantz) (Family: Euphorbiaceae) is a starchy fibrous root crop used for traditional desserts, salad dressing, soup thickening, binding agent in sausages, high fructose syrup, and textile industries [27]. The sweet type of cassava root can be boiled or roasted and eaten as fresh root, or minimally processed into various products. Cassava contains alkaloids, as well as flavonoids that have antioxidant and hypolipidemic effects [28], and glycosides that are potent for heart disease [29]. It has low content of nutrients such as protein (<2%), fat (<0.2%), and fiber (<4%) [30]. Most of the carbohydrate is present as starch (>32% of fresh weight) with smaller amounts of free sugars (less than 1% of fresh weight). It has rich dry matter (>80%) thus making it a good source of energy [27]. The root also contains minimal amount of micronutrients (e.g., iron, potassium, magnesium, copper, zinc, and manganese. It also has some anti-nutrients and toxic substances (e.g., cyanogenic glucosides), which together with their breakdown products (cyanohydrins and free hydrocyanic acid [HCN]) that are formed during processing, can inhibit the digestibility and intake of major nutrients [31]. The yellow root varieties contain a significant concentration of β-carotene (up to 1 mg 100 g− 1,dry-weight) [32].

#### **2.3 Carrot**

Carrots (*D. carota* L.) (Family: Apiaceae [Umbelliferae]) play a major role in human nutrition, because of their high dietary value [33]. Phytochemicals present comprise mainly of phenolic compounds (e.g., phenolic acids, such as *p*-hydroxybenzoic, caffeic, and chlorogenic; and flavonoids such as anthocyanins), carotenoids (a precursor to vitamin A formation, which is involved in vision, cell differentiation, synthesis of glycoproteins, mucus secretion from the epithelial cells, and overall growth and development of bones) [34], polyacetylenes, and ascorbic acid. These chemicals aid in the risk reduction of cancer and cardiovascular diseases due to their antioxidant, anti-inflammatory, plasma lipid modification, and anti-tumor properties [35]. Phenolic acids are the potentially bitter compounds found in carrot peels. The moisture content of carrot varies from 86 to 89% [36]. They are good source of carbohydrates and minerals like calcium, phosphorus, iron, and magnesium, and also contain protein (0.9%), fat (0.2%), carbohydrate (10.6%), crude fiber (1.2%), and total ash (1.1%) [36].

#### **2.4 Radish**

Radish (*R. sativus* L.) (Family: Brassicaceae) has high nutritional value and is consumed in salads, or cooked or salted together with other vegetables. The roots can also be processed as dried or canned pickles. The extracts of radishes have been used to treat stomach disorders, urinary tract infections, hepatic inflammation, cardiac disorders, and ulcers [37]. Various reports have recorded the antimicrobial, anticancer, antioxidant, and anxiety reducing properties of radishes. Phytochemicals present in radish include alkaloids, reducing sugar, flavonoids, glycosides, cardiac glycosides, tannins, saponin, protein, amino acid, terpenoids, and steroids [38]. Anthocyanin pigments provide the red color of roots, while a high potential to form isothiocyanates contributes to the pungent flavor and distinctive taste [39]. Radish is low in calories but has a high content of vitamin C which helps to build tissue, blood vessels, bones and teeth. Other vitamins (e.g., B6 and folate) and minerals (e.g., potassium, magnesium, calcium, iron, zinc, copper, sodium, and phosphorous) are also found in radish roots. Also, radish has fiber and roughage that is effective in the treatment of constipation.

#### **2.5 Potato**

Potato (*S. tuberosum* L.) (Family: Solanaceae) is a staple food that is often cooked or processed into edible products such as fries and chips. It contains several phytochemicals such as phenolics, flavonoids, polyamines, and carotenoids. These phytochemicals have beneficial effects on human health hence they are highly desirable in diet. The phenolics, together with amino acids present in potatoes, confer anti-oxidant protection towards tissue damage, reactive oxygen species and diseases like atherosclerosis, diabetes mellitus, renal failure, and cancer [40]. Nutritionally,

potato has complex carbohydrates (>20%) in the form of free sugars (with glucose and fructose as the principal monosaccharides and sucrose as the major disaccharide, crude proteins (>2.5%), crude fats (0.1%), crude fiber (0.6%), vitamins, and water (74%) and along with minerals (>0.8%), amino acids, and trace elements that include potassium, sodium, iodine, and magnesium, folic acid, pyridoxine, vitamin C, and iron. Additionally, potatoes contain glycoalkaloids, which are toxic steroidal glycosides and anti-nutritional substances. Although they play a role in plant resistance to bacterial and fungal diseases and pests, when in excessive amounts, they worsen taste, and a concentration above 200 mg·kg−1 of fresh weight has toxic effects on the human body [41].

### **3. Pre-storage treatment of root vegetables**

Freshly harvested root vegetables are metabolically active, and therefore still undergoing the physiological and biological processes of senescence and maturation. The rates of these processes are influenced primarily by the produce temperature. To prolong postharvest nutritional and quality (e.g., appearance, texture, and flavor) attributes, freshly harvested produce is often exposed to one or several optimal prestorage treatments that often work by; slowing down the senescence and maturation processes, reducing/inhibiting development of physiological disorders and growth of decay producing microorganisms, restricting enzymatic and respiratory activity, inhibiting water loss, and reducing ethylene production. Physical treatments include; heat [42], irradiation [19], coatings [15], pre-cooling [18] and curing [43].

Heat treatment methods that have been applied on carrot and potato include hot-water (sometimes accompanied by brushing), hot dry air, and steam [44–46]. These treatments activate or deactivate enzymatic activities that result in reduced effects on the phytochemical and nutrient content, besides reducing chilling injuries and controlling decay. The treatments can be of short (up to 1 h) or long-term (up to 4 days) duration, but they have high energy costs. Gamma irradiation and short wave ultraviolet radiation have been used to effectively inhibit growth and development of sprouts and microbial pathogens on potato [47, 48]. However, their use is still subject to strict legislation. Paraffin wax coat is often used in combination with the exclusion of oxygen or submerging roots in water or storing in an anaerobic environment that can inhibit the streaking of the cassava xylem tissue [20, 49].

Pre-cooling is the removal of field heat in the produce immediately following harvest by using methods that include; Hydro-cooling (i.e., submerging crops in cold water), forced-air cooling (i.e., cold air is directed directly through the crop at high velocity), room cooling (i.e., placing crops in a cold room where cold air passing through a fan) and package icing (i.e., placing crushed ice directly on top of the produce). The choice of the method depends on the product type and factors such as the airflow rate, air, and produce temperature, relative humidity, and the packing configuration [50]. Bunched beetroots (with tops) are pre-cooled to optimal level of below 4°C within 4–6 h of harvest, while mature beetroot are pre-cooled to below 5°C within 24 h after harvest. Forced-air cooling, prompt washing, and hydro-cooling in chlorinated water to under 5°C are essential to maintain carrot freshness. Bunched radish is often hydro-cooled in chlorinated water to an optimum level of 0–4.5°C [51]. Radish can also be pre-cooled using the package icing technique. Generally, room cooling has low or no cost involvement. Forced-air cooling has the risk of root desiccation. Hydro-cooling permits faster cooling but offers the moisture which some

*Phytochemical Changes in Root Vegetables during Postharvest Storage DOI: http://dx.doi.org/10.5772/intechopen.106554*

pathogens require to penetrate the skin of root vegetable [52]. Hence, it is recommended that washed root vegetables should be dried at room temperature before storage. Curing process, which is hardening the skin of potatoes and cassava under temperature and RH conditions that facilitate wound healing, depends on cultivar and on whether they are destined for industry or home consumption.

Surface treatment chemicals that include maleic hydroxide, α–naphthalene acetic acid, methylester, isopropyl N-(3chlorophenyl carbamate) chlorpropham) (CIPC) and 1, 2, 4, 5 tetra chloro-3nitrobenzene are applied on potatoes. These chemicals inhibit meristematic cell division and delay sprout development. Nevertheless, there are safety concerns about the potential toxic and carcinogenic properties of CIPC and its metabolites [53]. Safer alternatives include hydrogen peroxide plus (HPP) [54], 1,4-dimethylnaphthalene (1,4-DMN), essential oils, and ethylene [55]. Gaseous treatments include ozone that has been evaluated for postharvest disease control and other storage uses on potatoes and carrots [56, 57]. However, additional research is needed to define the potential and limits of effective use of ozone for postharvest treatment of whole and minimally-processed vegetables and fruits.

### **4. Storage systems of root vegetables**

Most fresh cassava cultivars deteriorate within 2–3 days after harvest and therefore, processing the roots into storable forms (through sun drying and fermentation) at the farm level is a better option for extending the shelf life and eliminating some toxic compound like cyanide. Some of the commonly used traditional methods include; coating of root with a paste of mud or earth, in-ground storage, field clumps, storage in a box or trench with alternative layers of moist sawdust or wood shavings and cassava roots, and storage in plastic bags [49, 58–60]. Advanced methods that are mainly used on export produce include cold storage/refrigeration at lower temperature range of 0–4°C, freeze drying, and modified atmosphere packaging [20, 49]. Nonetheless, financial and technical constraints have limited the use of advanced methods in many developing countries. Although a number of researches have been conducted on beet, carrot, and radish roots focusing on the potential uses as minimally processed ready-to-use, fresh-cut produce, or as ingredients of processed foods, information on the maintenance of freshness and quality of whole roots during storage is very limited [61]. However, freshly harvested bunched (with tops) and topped beets, carrots, and radish are usually stored between layers of moist sand, leaves, or sawdust in a box in cool place with condition of 0–4°C and 90–95% relative humidity (RH) [62]. The success of Controlled Atmosphere (CA) storage technology requires that the precise levels of CO2 and O2 gases are achieved and maintained within the storage facility. Where CO2 level is too high and O2 level too low, then the root vegetables may be irrevocably damaged [63]. However, there is little or no benefit from controlled atmosphere storage of these vegetable roots.

Potatoes are used for seed, ware, and processing and hence, storage requirements vary depending upon the purpose for which potatoes are to be used. Seed potatoes are required only at the time of planting; therefore, they need to be stored for longer. Generally, seed potatoes are stored at low temperatures (2–4°C). However, most local farmers store seed potato in simple and low-cost diffused light stores (DLS) that use natural indirect light with good ventilation to control excessive sprouting and to produce sprouts which are short, stout, green colored and with higher vigor [64]. Ware and processing potatoes are in demand throughout the year and hence both

short- and long-term storage are needed. Ware and processing potatoes are stored at higher temperatures (8–12°C at 85–90% RH) [65]. Majority of smallholder farmers use traditional storage methods of ware potato. These include piling on the floor or corner in houses, dark stores, DLS, covering potato deep in the soil, stacking tubers in sacks, and heaping potato tubers under the tree shades. Majority of these methods allow keeping potato in good quality for a short period of 2–5 weeks only, depending on the potato variety [66]. Ambient ware potato storage units are also in use and can maintain the marketability of ware potato up to 9 weeks. While advanced ware potato storage methods like evaporative cool storage and cold storage exist, they are not used in most developing countries due to high costs.


**Policies and Strategies in Sexual and Reproductive Health**

Editors

**Juan Miguel Mart´ınez Galiano Miguel Delgado-Rodr´ıguez**

MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin

*Editors* Juan Miguel Mart´ınez Galiano University of Jaen Spain

Miguel Delgado-Rodr´ıguez University of Jaen Spain

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This is a reprint of articles from the Special Issue published online in the open access journal *International Journal of Environmental Research and Public Health* (ISSN 1660-4601) (available at: https://www.mdpi.com/journal/ijerph/special issues/Policies Strategies Sexual Reproductive Health).

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**3. Results and Discussion**

This new class of chloro-substituted pyrazin-2-amine ligands given in Chart 1 were made to react with cupric bromide (CuBr2), either by refluxing in a 1:1:1 (*v*/*v*/*v*) mixture of acetone (Ace), ethanol (EtOH) and acetonitrile (MeCN) or 1:5 (*v*/*v*) mixture of Ace:EtOH to afford the desired Cu(I)Br complexes, via an in situ redox process, according to Scheme 1. An excess of pyrazine ligand was used to act as ligand and auxiliary base for the HBr liberated during the reduction of CuBr2 to CuBr by acetone [70]. The reduction was accompanied by a color change from a deep blue-green solution characteristic of Cu(II) ions, to a clear, yellow solution upon refluxing for several minutes. In total, eight different Cu(I)Br coordination complexes obtained from the combination of these six ligands will be discussed.

**Chart 1.** List of chloro-substituted pyrazin-2-amines and numbering scheme used throughout: 2-amino-3-chloropyrazine (**1**), 2-amino-5-chloropyrazine (**2**), 2-amino-6-chloropyrazine (**3**), 2-amino-5,6- dichloropyrazine (**4**), 2-amino-3,6-dichloropyrazine (**5**), and 2-amino-3,5-dichloropyrazine (**6**).

**Scheme 1.** General synthetic route to Cu(I)-complexes of ligands **1**–**6** via an in situ redox process from CuBr2, and the nomenclature used.

X-ray quality crystals of the complexes were obtained by slowly concentrating the reaction mixtures by controlled evaporation. Interestingly, **2c**·CuBr was only obtained from a 1:5 (*v*/*v*) Ace and EtOH reaction mixture, together with **2b**·CuBr. The concomitant polymorphism did not allow the isolation of **2c**·CuBr as a phase pure material; however, **2b**·CuBr could be prepared independently by alternative methodologies in moderate yield. Moreover, attempts to recrystallize the mixture of **2c**·CuBr and **2b**·CuBr from MeCN afforded only complexes **2a**·CuBr and **2b**·CuBr. This suggests the **2c**·CuBr is only somewhat stable when prepared from a 1:5 (*v*/*v*) Ace:EtOH mixture and readily dissociates in the polar aprotic solvent MeCN. Optical microscopy could be routinely used to distinguish the different color and crystal habits of the three different polymorphs of (**2a**–**c**) CuBr (See Figure S1). Powder X-ray diffraction methods were used to demonstrate the solid-state structures and estimate the phase purity of the bulk material by using Pawley full pattern fittings. The FT-IR spectra of the isolated complexes were compared to the respective ligands, and display two specific regions from 3500–2800 cm−1 and 1200–400 cm−1 for the hydrogen-bonded N–H stretching [71] and fingerprint regions, respectively, which are distinctive for each ligand and complex (see Figures S10–S16).

In general, reactions between donor ligands (L) and CuX (X= Cl, Br, I) yield complexes with formula Cu*n*X*n*L*m*, that display diverse structural topologies, containing rhomboid dimer, zigzag polymer, staircase polymer, closed cubane, and hexagon clusters, have been reported in the literature [72]. The structural diversification stems from the very nature of the ligand coordination modes and the tendency of copper halides to form clusters via μ2- and μ3-halide bridges [73]. In our eight complexes, we obtained three topologies exclusively, namely staircase polymer (**1**·CuBr, **2a**·CuBr, **2c**·CuBr, **4**·CuBr, **5**·CuBr, and **6**·CuBr), rhomboid dimer (**2b**·CuBr), and zigzag polymer (**3**·CuBr), as depicted in Figure 1. The staircase and rhomboid structures feature well-known Cu···Cu distances (Cuprophilic interactions) [74], ranging from 2.7547(13) to 3.086(4) Å, but will not be discussed further in the text.

The complexes **1**·CuBr and **2a**·CuBr both crystallize as clear, pale-yellow or colorless needles in an orthorhombic space group, *P*na21 and *P*212121, respectively. Both contain discrete 1D polymeric chains of the catenated (μ3-bromo)-CuI 'staircase' that run parallel to the *c*-axis and *a*-axis in **1**·CuBr and **2a**·CuBr, respectively. In these chains, the Cu(I) ions have tetrahedral geometry, coordinated by three bromines and the pyrazine N1-atom. Since the pyrazine N4-atom is not involved in the N–Cu bond formation, it plays a central role in the HB formation involving a C2-amino group of an adjacent chain. The orthogonal arrangement of the discrete 1-D polymeric chains leads to a herringbone packing structure in both **1**·CuBr and **2a**·CuBr, as illustrated in Figure 2. The N4···H–N HBs in **1**·CuBr of 2.245(11) Å, [∠N4···H–N = 155.6(9)◦] are shorter than in **2a**·CuBr [2.349(7) Å, ∠N4···H–N = 133.4(5)◦]. The XBs in **1**·CuBr and **2a**·CuBr complexes are, however, more comparable at 3.465(3) Å [∠Br···Cl–C = 165.4(3)◦] and 3.509(3) Å [∠Br···Cl–C = 159.5(3)◦], respectively. This network of HBs and XBs does lead to a complex molecular packing that extends in three dimensions.

**Figure 1.** The three structural topologies realized in the Cu(I)-complexes of **1**–**6**, (**a**) catenated (μ3-bromo)-CuI 'staircase' polymer, (**b**) Cu2Br2 rhomboid (μ2-bromo)-CuI dimers, and (**c**) zigzag polymer (μ2-bromo)-CuI chains.

The complex **6**·CuBr crystallizes in a monoclinic *P*21/*c* space group, and is composed of 1D polymeric chains of the catenated (μ3-bromo)-CuI 'staircase' that run along the shortest unit cell *a*-axis. The asymmetric unit contains one bromide anion and a one Cu(I) cation coordinated by the sterically less hindered N1-atom of **6**. Not surprisingly, the C3 and C5 chloro-substituents vicinal to the N4-atom render this ring nitrogen Cu-coordination passive. The orthogonal arrangement of the discrete 1D polymeric chains leads to a herringbone packing structure that is similar to **1**·CuBr and **2a**·CuBr (for **6**·CuBr, see Figure S2). The 1D chains are aligned by a more extensive network of XBs, afforded by the C3- and C5-Cl substituents (C3–Cl···Br–Cu [3.4794(14) Å, ∠Br···Cl–C = 162.44(19)◦], C5–Cl···Br–Cu [3.4178(14) Å, ∠Br···Cl–C = 175.34(19)◦]) and longer N4···H–N of 2.511(4) Å, [∠N4···H–N = 135.8(3)◦] HBs, compared to **1**·CuBr and **2a**·CuBr.

The N1–Cu mode of coordination realized in **1**·CuBr, **2a**·CuBr, and **6**·CuBr allows the vicinal C2-amino group hydrogen and a Cu(I) bound bromide to form cyclic N–H···Br–Cu HBs, with distances varying from ca. 2.609(7)–2.774(2) Å [∠Br···H–N = 146(1)◦–168.9(4)◦], within the discrete polymeric (μ3-bromo)-CuI 'staircase' chain (See Figure S3). These cyclic intra-chain N–H···Br HBs afford a pseudo-helical type arrangement of the pyrazine ligands along the polymeric (μ3-bromo)-CuI 'staircase' backbone. The HBs, in combination with the C–Cl···Br–Cu XBs from neighboring chains, aids the stabilization of the catenated (μ3-bromo)-CuI 'staircase' polymeric chains in these complexes.

The complexes **4**·CuBr and **5**·CuBr crystallize in a triclinic *P*-1 and monoclinic *P*21/n space groups, respectively. In both complexes, the catenated (μ3-bromo)-CuI 'staircase' motif is preserved, however, the tetrahedral Cu(I) centers are coordinated by three bromides and a pyrazine N4-atom. In the case of **4**·CuBr, it crystallizes with an additional pyrazine molecule in the asymmetric unit that is not involved in coordination with the Cu(I) centers. The N4–Cu coordination mode found in both complexes allows the C2-amino group to participate in hydrogen-bonding with a neighboring pyrazine in a self-complimentary N–H···Npz pyrazine dimer. The resultant hydrogen-bonded dimers in **4**·CuBr and **5**·CuBr are described by the graph set notation R22(8), with HB parameters of ca. 2.308(12) Å, [166.4(7)◦] and 2.138(5) Å [160.1(3)◦], respectively (Figure 3). These Watson–Crick-like base pairing structures are characteristic of aminopyrazine derivatives [75,76]. The R22(8) hydrogen bonding in **4**·CuBr and **5**·CuBr leads to essentially linear chains that pack into laminar 2D polymeric sheets held together by the polymeric (μ3-bromo)-CuI 'staircase' motif. The non-coordinating pyrazine in **4**·CuBr forms an additional set of R22(8) hydrogen-bonded dimers that cross-link the 2D sheets via non-cyclic

N–H···N-ring hydrogen bonds [2.219(11) Å ∠N–H···N4, 177.7(8)◦], into a 3D structure shown in Figure 3a. Although **4**·CuBr and **5**·CuBr lack the intra-chain cyclic N–H···Br–Cu HBs (see Figure S4) found in **1**·CuBr, **2a**·CuBr, and **6**·CuBr, a network of non-cyclic inter-chain N–H···Br–Cu and C–H···Br–Cu HBs are established between neighboring chains in **5**·CuBr or the non-complexed pyrazine in **4**·CuBr. Overall, the N–H···Br–Cu and C–H···Br–Cu HBs together with the C–Cl···Br–Cu, and C–Cl···Cl–C XBs stabilize the polymeric μ3-bromo 'staircase', and further cross-link the laminar 2D polymeric sheets into complex 3D structures. Notwithstanding the structural similarities between **4**·CuBr and **5**·CuBr, as determined by single-crystal X-ray diffraction, the solid-state structure of **4**·CuBr could not be demonstrated in the bulk material, as determined by powder X-ray diffraction. Full pattern Pawley analysis of **4**·CuBr suggests that the bulk material is effectively isomorphous with **6**·CuBr (See Table S6 and Figure S8). This suggests that additional polymorphs may exist where the Cu(I) center is coordinated by the sterically more congested N1 in **4**. This possibility has also been observed in **3**·CuBr, and polymorphism has been demonstrated in **2**(**a**–**c**)·CuBr, as described below. Despite repeated attempts, under different conditions, alternative single-crystal structures of Cu(I) complexes of **4** have still not been realized.

**Figure 2.** The herringbone packing arrangement of the discrete 1D polymeric chains of (**a**) **1**·CuBr, (**b**) and **2a**·CuBr. The red- and black- dotted lines represent hydrogen and halogen bonds, respectively.

**Figure 3.** The R22(8) hydrogen-bonded ring motif realized in the crystal packing of (**a**) **4**·CuBr, and (**b**) **5**·CuBr. Red dotted lines are N–H···N R22(8) and N–H···Br–Cu hydrogen bonds, and black are C–Cl···Cl–Cu halogen bonds.

The three polymeric structures **2b**, **2c**·and **3**·CuBr all contain bridging μ2-*N*,*N'* pyrazine ligands, and display the three (CuBr)n structural motifs outlined in Figure 1. Complex **2b**·CuBr crystallizes in the orthorhombic space group *Pbcn* as amber, prismatic blocks (See Figure S1a). In this complex, the pyrazine ligands are μ2-*N*,*N'* bridging between Cu2Br2 rhomboid dimer units to afford a distorted tetrahedral coordination geometry at the Cu(I) ion formed by two symmetry-equivalent bromines, and the N1- and N4-atoms of two different pyrazine ligands. This leads to a 2D dimensional honey-comb sheet that propagates in the *ab* plane, as illustrated in Figure 4a. The honey comb structure is similar to the [CuCl(μ-2,5-dimethylpyrazine-*N*,*N*)]n structure reported in the literature [77]. Adjacent layers are held together by C5–Cl···Br–Cu [3.5105(7) Å, ∠Br···Cl–C = 161.83(8)◦] XBs and N–H···Br–Cu [2.6402(2) Å, ∠Br···H–N = 159.28(14)◦] HBs, as given in Figure 4b. Moreover, these HBs and XBs, together with steric effects, prevent the formation of a catenated μ-bromo-CuI motif, as in the staircase polymers previously mentioned.

**Figure 4.** (**a**) 2-D Honey comb motif of **2b**·CuBr, and (**b**) 3-D packing unit displaying hydrogen (red dotted lines) and halogen bonds (black dotted lines) between 2-D sheets.

The bright yellow, needles of **2c**·CuBr crystallize in the monoclinic space group *P*21/*n*. The asymmetric unit consists of a Cu(I) ion; one bromide and one half of a pyrazine ligand. The C5-chlorine and C2-amine substituents exhibit a positional disorder with 50:50 occupancies. The distorted tetrahedral coordination environment of Cu(I) consists of one pyrazine nitrogen and three symmetry equivalent bromide anions. Ligand **2** is μ2-*N*,*N'* bridging to yield a 2D polymeric sheet containing the catenated (μ3-bromo)-CuI 'staircase' chain structure, as shown in Figure 5. The polymeric structure of **2c**·CuBr is similar to that found in the 2D coordination polymer of 2-aminopyrazine with CuI (i.e., [Cu2I2(2-aminopyrazine)]*n*) [78] and [2(μ-2,5-dimethylpyrazine-*N*,*N*)Cu2]n where X = Br, I [77]. The adjacent sheets are linked by N–H···Br–Cu [2.6054(17) Å, ∠Br···H–N = 175(4)◦] interactions between the C2-amino group and a Cu(I)-bound bromide. As a result of positional disorder, the C–Cl bond length associated with the 50% occupancy is close to the standard C–Cl bond distance, and results in a weak C5–Cl···Br–Cu [3.582(15) Å, ∠Cl···Br–Cu = 103.9(9)◦] 'contact'. These weak interactions are likely triggered by the N–H···Br–Cu interactions between the neighboring molecules in this laminar structure. Due to the disorder, there are possible HB and XB interactions that could alternate along a plane that passes through the amino- and chloro-substituents of the pyrazines of adjacent sheets, thus forming moderately short Cl···Cl halogen contacts with RXB = 0.88. These HBs and XB interactions

further supports the catenated (μ3-bromo)-CuI 'staircase' motif as a common structural feature in these complexes.

**Figure 5.** (**a**) Here, 2D polymeric sheet structure of **2c**·CuBr, and (**b**) the hydrogen and halogen bonds (black dotted lines) between sheets in the laminar structure. Note: the disordered atoms were not omitted to reflect the discussion.

The complex **3**·CuBr, crystallized in the monoclinic space group *P*21/*n*. The distorted tetrahedral coordination environment of the Cu(I) is composed of two symmetry-related bromides and two crystallographically different N-atoms from two distinct pyrazine ligands. The Cu(I) ions are bridged by μ2-*N*,*N'* pyrazine ligands, forming 1D linear chains that run along the *c*-axis as illustrated in Figure 6a. These chains are further linked into a 2D sheet structure by polymeric (μ2-bromo)-CuI-Br chains along the *a*-axis. The 2D layers are not flat, but instead adopt a slightly corrugated pattern because of the ∠N–Cu–N = 136.6(4)◦ at the distorted tetrahedron at the Cu(I) ion, as shown in Figure 6b. Two types of interactions assemble the layers into a 3D structure. First is the hydrogen bonding between a C2-amino group and Cu(I)-bound bromide from an adjacent layer [2.3615(10) Å, ∠Br···H–N = 164.2 (7)◦; 2.4846(12) Å, ∠Br···H–N = 158.9(6)◦], to afford a R22(8) ring motif from a set of two N–H···Br HBs. The second interaction is C6–Cl···Br–Cu halogen bonds [3.527(3) Å, ∠Br···Cl–C = 158.8(4)◦] between a chlorine on the pyrazine ring and bromide coordinated to Cu(I) on an adjacent layers, as shown in Figure 6b. Similar to the (μ3-bromo)-CuI 'staircase' motif, the μ2-bromo polymeric chains found in **3**·CuBr is fully stabilized by the network of HB and XBs, and is likely adopted because of the steric demands of the N1 coordination, compared to the more accessible N4-coordination mode in ligand **3**.

**Figure 6.** (**a**) Here, 2D Layered structure of **3**·CuBr, and (**b**) 2-D layers stack viewed along the a-axis. Red dotted lines are N–H···Br–Cu hydrogen bonds, and black are C6–Cl···Br–Cu halogen bonds.