Sep. 23, 2024
The close ionic radii and oxidation state of Pb 2+ and Sr 2+ make the former toxic, especially for bones. It is well-known that poisoning by free lead cations affects its accumulation in the skeleton. Moreover, because it has an oxidation state of 2+, it can replace Zn 2+ in the biosynthesis of heme, causing anemia.
You will get efficient and thoughtful service from Yayang.
Alternatively, completely unsubstituted cyclen (CN4) [ 49 ] and its pyridine analog (CN4) L3 [ 52 ] coordinate Pb 2+ so as to leave the space for LP, the addition of one coordinating pendant arm in L1 [ 52 ] still allows one-side coordination with shortened Pb&#;N bonds on the side opposite to LP. Further introduction of four groups, TCMC, DOTA, THP-cyclen, causes a significant decrease in differences between values of bonds&#; lengths Pb&#;N and Pb&#;O ( ). Moreover, from Pb&#;cyclen to Pb&#;THP&#;12aneN4 and from Pb&#;L3 to Pb&#;L2 [ 52 ], a small but regular decrease in logβ (PbL) occurs ( ). Such an effect is caused by the transition from hemidirected to holodirected LP [ 49 , 55 ] being thermodynamically disadvantageous. Similarly, in complex with EDTA LP is hemidirected, but upon ligand&#;s modification to EEDTA and EGTA LP of Pb 2+ becomes inactive, leading to a large drop of logβ, while analogous modification does not cause such drastic break for Sr-EDTA and Sr-EGTA (Sr 2+ and Pb 2+ are similar regarding ionic radii [ 46 ]). Furthermore, basic nitrogen atoms bring covalent impact to the interaction with Pb 2+ enhancing LP&#;s activity. This induces logβ drop upon substitution of NH-groups in cyclen by O-atoms [ 49 ]. However, accompaniment of N-donors by O-containing pendant groups increases the stability of formed complexes Pb&#;cyclen&#;Pb&#;DOTA or Pb&#;TCMC, Pb&#;en&#;Pb&#;EDTA.
The presence of the lone electron pair (LP) 6s 2 in the electron shell of Pb 2+ causes, in some cases, asymmetric coordination. The stereochemical activity of LP can appear in different degrees and has been debated for a long time [ 48 , 49 , 50 , 51 , 52 , 53 ]. In addition to the classical consideration of bonds&#; lengths with the closest donor atoms in complexes with polyamines due to the X-ray single-crystal analysis [ 48 , 49 ], various quantum chemical calculations to reveal transition 6s 2 -6sp [ 51 ] or localize excessive electron density in Pb 2+ &#;s coordination environment [ 53 ] were performed. One of the major empirical conclusions in many works is that high CNs of ligand (>8) provide the lack of activity of LP (holodirected), while in complexes with low CNs (<6), LP is well pronounced (hemidirected). Namely, for smaller ligands, such as EDTA and ACAC [ 49 , 50 ], an obvious space in the first coordination sphere is observed. The latter is taken as a direct indication of hemidirected character. Other ligands such as 18-crown-6, CHX 2 -18-crown-6 [ 54 ], and EGTA [ 51 ] allow chelation of cations with longer interatomic distances where the basic atoms are distant from each other and correspondingly cannot crowd together on one side of a cation upon its coordination. In these complexes, Pb&#;L bonds are longer and differ less between each other, very likely indicating LP&#;s inactivity and uniform distribution of electron density of LP around the cation with regard to the distant location of donor atoms. In the frame of such consideration, holodirected or hemidirected behavior of LP in lead complexes with TCMC and DOTA are still highly controversial. Hereinafter, all ligands discussed through the paper are shown in .
Besides organic ligands, other carriers, such as liposomes [ 87 ] and fullerenes [ 34 ], were also considered. Such kinds of transporters can provide the absence of release of daughter radionuclides after alpha decay due to recoil. On the other hand, the recoil of the 212 Pb nucleus from 224 Ra was used to incorporate 212 Pb into fullerenes (C60) for the synthesis of labeled fullerenes 212 . It is of interest that Pb@C60 [ 34 ] also had 213 Bi originating from 225 Ra that was present as an impurity in 224 Ra, while no 225 Ac was found. The latter was caused by a lack of recoil in the decay of 225 Ra but sufficient upon formation of 213 Bi. The feasibility of this labeling path was demonstrated, but the yields did not exceed 1%. Despite no activity being detected in bones, meaning stability of 212 Pb@C60 regarding dissociation in a live organism, modification of fullerenes is required since in vivo experiments revealed retention in the spleen and liver.
Another related class of organic compounds evaluated for application as part of radiotherapeutics with 212 Pb is phosphonate ligands, including other functionalized cyclen DOTMP and EDTA analog EDTMP. Similar to [ 212 Pb]Pb&#;DOTA complex, [ 212 Pb]Pb&#;DOTMP releases 212 Bi upon the decay of 212 Pb, leading to renal accumulation of freed bismuth, while no released of 212 Bi were found when [ 212 Bi]Bi&#;DOTMP was injected [ 86 ]. However, both bismuth and lead complexes with DOTMP demonstrated higher stability in vivo compared to chelates with acyclic ligand EDTMP [ 86 ].
Other cases of complexation of Pb 2+ by azacrown-ethers DOTA, PEPA, and HEHA were suggested for analytical purposes, namely, determining the number of chelator molecules per protein molecule after conjugation [ 85 ]. However, it was not the case for TETA as a result of low logβ (Pb&#;TETA), causing the lack of competition with Arsenazo III for Pb 2+ .
Complexes with other azacrown ethers NOTA and TETA were tested for stability in an acidic medium [ 82 ]. Both complexes were shown to dissociate in contrast to Pb&#;DOTA. In addition, the synthesis of [ 212 Pb]Pb&#;NOTA was completely unsuccessful, with <10% chelated at pH6 [ 13 ]. In general, NOTA, being the smallest among azacrowns, is more appropriate for cations of a smaller radius such as Cu 2+ (R(CN6) = 0.73 Å) or Ga 3+ (R(CN6) = 0.62 Å vs. 1.19 Å for Pb 2+ [ 46 ]) [ 83 ]. That is why hampered complexation of Pb 2+ as well as low stability are coherent. Moreover, replacement of one acetic arm by ethylene-aminodiacetic (NETA) improves the stability in vitro; when challenged with serum proteins, Pb&#;NETA keeps 100% intactness in 11 days; and in vivo, fast clearance and the lack of retention in any organs [ 61 ]. The significance of the ethylene-aminodiacetic arm in NETA for chelation of Pb 2+ was shown upon ineffective modifications: its elongation till propylene-aminodiacetic pendant arm (NPTA) [ 61 ] or bifunctionalization with Bn-SCN-moiety (C-NE3TA) [ 84 ]. The stability of both Pb&#;NPTA and Pb&#;NE3TA dropped in vitro [ 84 ] as well as in vivo [ 61 ]. Due to the lack of structural data for the discussed complexes, one can suggest that dislocation of coordinating sites in NETA provides the most effective chelation of Pb 2+ and any change, such as an increase in the distance between them or decrease in the stereochemical availability via bulky Bn-SCN bifunctional group crucially affects the stability of the complexes formed.
Regarding the large difference in the basicity of DOTA and TCMC, a comparison of the role of the medium&#;s acidity on the stability of complexes with Pb 2+ is important. It was shown that upon the incubation of labeled mAbs&#; conjugates [ 203 Pb]Pb&#;DOTA&#;CC49 and [ 203 Pb]Pb&#;TCMC&#;CC49 in the solutions with varied pH, the half-dissociation time for the former is 10&#;15 h at pH 2 and 150 h for the latter [ 64 ]. According to [ 57 ], the acid-catalyzed dissociation of Pb&#;DOTA begins from the protonation of the carboxylic group, and then this proton migrates onto macrocyclic nitrogen. Less basic acetamide groups of TCMC compared to acetic in DOTA provide lesser affinity to protons at the beginning, leading to Pb&#;TCMC complex inertness in an acidic medium [ 64 , 81 ]. However, both complexes demonstrated similar stability in the presence of competing chelating agents: 100% after 1 d. Further, the cation is released from both but from Pb&#;DOTA at a higher rate [ 64 ].
Beta-decay of 212 Pb accompanied by electron conversion yields the highly ionized state of a daughter atom of 212 Bi. The latter provides Bi&#;L bonds&#; breaks in complexes with DOTA [ 77 ] and release of ~36% of 212 Bi from the complex, finding confirmation in many in vivo experiments [ 75 , 76 , 77 ]. A deviation from the equilibrium ratio of A( 212 Pb)/A( 212 Bi) is observed. This is especially true in the case of kidneys, a characteristic organ for unbound Bi 3+ retention. A comparison of the biodistribution of the different isotopes 212 Pb, 203 Pb, and 205/6 Bi [ 75 , 76 ] was carried out. As a result, increased 212 Bi content was detected in kidneys upon injection of 212 Pb complex and correspondingly unbound cation in urine, while with 203 Pb and 205/6 Bi, accumulation of Pb 2+ or Bi 3+ in kidneys was not detected, and only complexed forms of radioactivity were found in urine. This proves the influence of 212 Pb&#;s decay on the fate of daughter 212 Bi. Moreover, even after incubation of [ 212 Pb]Pb&#;DOTA&#;biotin in an aqueous solution for 4 h, detection of ~30% of unbound (apparently released) bismuth cation is possible [ 76 ]. Concerning the [ 212 Pb]Pb&#;TCMC complex, it was mentioned that 16% of 212 Bi is released [ 78 ]. Moreover, by this time, a mathematical model for predicting the possible release of daughter radionuclide was developed and experimentally tested [ 79 ]. However, recently, PSMA ligands were labeled with 212 Pb via bifunctional DOTA and TCMC [ 80 ], and a comparison of biodistribution of 212 Pb and 212 Bi did not reveal differences.
However, direct comparisons of conjugates DOTA&#;mAb and TCMC&#;mAb have shown that the latter binds cation more effectively [ 64 ] ( ). Long manipulations with eluate from 224 Ra/ 212 Pb as well as synthesis and purification procedures of labeled compounds are possible due to the long half-life of 212 Pb. It is noteworthy that in an exhaustive majority, synthesis at 37 °C for 30&#;60 min requires the purification via exclusion chromatography from unbound cation that was preliminarily chelated by DTPA or EDTA. This is a necessary step because of incomplete cation binding at low temperatures.
Currently, only two chelators were studied in detail for 212 Pb chelation, DOTA and TCMC (DOTAM) [ 62 ], including immunotherapeutics based on mAbs (monoclonal antibodies) that are heat-sensitive ( ). Both these ligands are characterized by a low complexation rate at room temperature (rt), and formed complexes slowly dissociate, i.e., are inert. As soon as ligands are structurally close, both complexes form analogous crystal structures ( ) and logβ values ( ) despite significant variation in affinity to protons pKa (DOTA) = 28 [ 63 ] vs. pKa (TCMC) = 14.86 [ 50 ]. In both structures, the coordinating polyhedron is a tetragonal antiprism formed by cyclen&#;s nitrogen and oxygens of acetic/acetamide groups [ 50 , 51 ].
To the best of our knowledge, DTPA was not evaluated for the chelation of 212 Pb in target radiopharmaceuticals. However, modifications of DTPA were considered for 212 Pb chelation for nuclear medicine [ 61 ]. Being flexible, acyclic ligand DTPA was rigidified via cyclization of the main backbone, producing AZEP-DTPA and PIP-DTPA. Complexes of 203 Pb 2+ with both ligands have demonstrated high stability in vitro in the presence of serum proteins, which proves the positive influence of cyclic fragments introduction into DTPA. However, in vivo experiments performed in normal mice with piperidine derivative (PIP-DTPA) showed quicker pharmacokinetics, indicating fast clearance and indirectly revealing in vivo stability in contrast to AZEP-DTPA. Furthermore, in order to evaluate the applicability of ligands for 212 Pb chelation in radiopharmaceuticals, it is expedient to study the binding of these ligands with daughter radionuclide 212 Bi. In bismuth complexes, the effectivity of PIP-DTPA is more pronounced than in lead complexes; upon injection of Bi&#;AZEP&#;DTPA, kidneys retained 5&#;10 fold higher levels of radioactivity than upon Bi&#;PIP&#;DTPA application.
Among earlier works regarding the therapeutic application of 212Pb, a series of papers [88,89,90,91] was dedicated to the assessment of various forms labeled by 212Pb: labeled liposomes [91], sulfur colloids [90], and colloids of iron&#;s hydroxides [89]. Cell lines of ovarian cancer and xenografted mice with epithelial ovarian and Erlich&#;s cancer for in vivo tests were used. In this case, an intraperitoneal (I.P.) injection was used to study the character of abdominal tumors. The non-uniform distribution of colloids caused by the inappropriate size of colloids led to the sorption of radioactivity on the colon and corresponding necrotic lesions. The latter caused adverse effects on the gastrointestinal system and bone marrow. Although 212Pb was injected without targeting moiety, only chelated by DTPA study of cytotoxicity in vitro revealed dose-depending burdens of cells&#; chromosomes [89], meaning that even the presence of 212Pb in the surrounding medium matters. In addition, 15 and 50 µCi (555 kBq&#; kBq) in the form of [212Pb]Fe(OH)2 were effective for tripling the survival period of mice, whereas 24% had complete remission.
The majority of the further research in this field was carried out with targeting molecules: peptides and monoclonal antibodies (mAbs) that possess selectivity for definite cells. To safely apply highly toxic alpha-radiation, the determination of a range of applicable doses is required at the beginning [75].
The range of tolerant doses was estimated in various papers [28,65,75]. It was empirically shown that the effectiveness of radioimmunotherapy (RIT) by 212Pb depends on the size and/or age of the tumor xenografted. The normal mice, as well as mice implanted with erythroleukemia [75] and ovarian cancer [65], were treated by respective antibodies labeled by 212Pb ( ). The activity levels of 20 [75] and 40 µCi [65] (740 and kBq) were found to induce fatal marrow toxicity in normal mice. Nevertheless, 10&#;20 µCi (370 and 740 kBq) caused complete remission for smaller size tumors if the therapy was started on the third day after cancer cells&#; inoculation [65]. Other cases of treatment initiation on the 8&#;14th day [75] and later when tumor volume reaches >15 mm3 [65] yielded only a partial decrease in its size. Moreover, for large burdens of 146 mm3, no effect was detected. Apparently, this was caused by the lack of crossfire effect for alpha-emission compared to beta-emission, causing the therapy of large solid tumors by 212Pb to be ineffective. Interestingly, the presence of β-particles (E(βmax) = 574 keV) from 212Pb itself did not impact the crossfire effect. It could be the sequence of the quantity of the applied activity of 212Pb compared to GBq levels of activities for traditional β-emitting radiopharmaceuticals with 177Lu (E(βmax) = 498 keV) and 90Y (E(βmax) = keV) [92,93].
For in vivo mice experiments, only doses lower than 20&#;40 µCi (740&#; kBq) were used [23,66,68,94,95,96]. However, in [24], for the treatment of palpable melanoma, 50&#;200 µCi ( kBq&#; kBq) of 212Pb were applied. Renal toxicity for 100 and 200 µCi ( kBq and kBq) was revealed in histological tests of the kidney&#;s cortex, while no external symptoms were observed. Therefore, dose-limiting organs were kidneys, not bone marrow, compared to the aforementioned papers. This was related to the affinity of the antibody to kidneys. It is noteworthy that these 100 and 200 µCi ( kBq and kBq) were not only less toxic but also caused tumor-free survival with a 2&#;3-fold elongation of mean survival.
Monoclonal antibodies labeled with 212Pb were shown to be cleared without retention in organs, and, correspondingly, no irradiation of healthy tissues occurred. However, in the case of injection in xenografted mice, no significant myelotoxicity was found. Bone marrow toxicity was associated with metabolic processes following the internalization of mAb in malignant cells [75]. This degradation of mAb includes transportation to the liver, the second organ of radioactivity accumulation after bone. The latter retained Pb2+ after acid-mediated dissociation of [212Pb]Pb&#;DOTA&#;mAb during its degradation. That is why TCMC, being more stable in the acidic conditions complexes [64], was a preferred alternative for DOTA as part of 212Pb radiotherapeutics.
After conjugation of TCMC with trastuzumab, [212Pb]Pb&#;TCMC&#;trastuzumab was thoroughly studied [68,94,95,97,98,99]. One of the first detailed analyses of therapeutic efficacy of [212Pb]Pb&#;TCMC&#;trastuzumab towards two types of HER2-expressing tumors was performed in [68]. According to in vitro experiments with cell lines, the advantage of 212Pb over 212,213Bi was established. MTD was stated to be 20&#;40 µCi (740 kBq&#; kBq) owing to survival and weight loss. This value agrees well with earlier published estimations [65,75]. Furthermore, even upon fractionated injection of 30&#;40 µCi (110 kBq&#; kBq) by 10 µCi (370 kBq), these values led to a decrease in effectiveness and shortened survival [68]. The best results in single or fractionated injections were an extension of the survival period by 2&#;4 times depending on the dose injected. It is noteworthy that regarding previous results of [65], this therapeutic study was demonstrated on 3- and 5-day colon cancer tumors.
Further, this group studied the effects of combined application of chemotherapeutics such as gemcitabine [94] and paclitaxel [95] with [212Pb]Pb&#;TCMC&#;trastuzumab. Different schemes of chemo and radioimmunotherapeutics were varied in vivo, and analyses of the cell mechanisms managing their effects were attempted [20,97,98]. The research series described above [68] was carried out on a human colon carcinoma model in xenografted mice. The cells possess affinity towards Herceptin (commercial name of trastuzumab), and this cancer can form a disseminated peritoneal disease. It was shown in vivo that a combination of radiosensitizing gemcitabine [94] and paclitaxel [95] with target radiotherapy gives a synergistic effect, whereas such a therapeutic effect cannot be reached by these therapeutics separately and without targeting moiety. Moreover, it was shown that treatment is effective even with 5 and 10 µCi (180 and 360 kBq) of 212Pb. In [94], four methods of treatment were tested concerning the action of chemotherapeutics, along with the results of a previous method. The best results were achieved when four doses of gemcitabine (1 mg) and two doses (10 µCi, or 360 kBq each) of [212Pb]Pb&#;trastuzumab [94] or 0.6 mg paclitaxel and 10 µCi (360 kBq) of 212Pb [95] were applied in the definite order. These approaches provided &#;10 and 4 fold prolongation of median survival of xenografted mice compared to non-treated or treated with [212Pb]Pb&#;trastuzumab alone [94,95]. Tumor cell analysis revealed that upon injection of [212Pb]Pb&#;trastuzumab alone [97] or with paclitaxel [20] or gemcitabine [98,99], genes responsible for cell cycle arrest, apoptosis, and corresponding mechanisms leading to cell death or depression of successful reproduction were induced. Surprisingly, no induction of genes involved in DSB-repair was observed, while expression of genes repairing single-strand breaks was increased [97]. Moreover, in cases with [212Pb]Pb&#;trasuzumab alone or accompanied by paclitaxel, no recovery of the cell cycle was observed, while treatment with non-specifically targeted 212Pb was shown to cause repairable cell cycle [20].
Similar to TCMC&#;trastuzumab bioconjugate, DOTAMTATE (TCMC&#;TATE) was preclinically studied for therapy of neuroendocrine tumors (SSTR-positive) labeled with 212Pb [100] as a single treatment agent and in combination with chemotherapeutic 5-fluorouracil [73]. This study confirmed tolerated doses of 20&#;40 µCi (740 kBq&#; kBq) of [212Pb]Pb&#;DOTAMTATE. Moreover, different regimes of fractionated injection of radioactivity with varied periods between injections showed that application of 3 × 15 µCi led to 100% survival of normal mice in contrast to 50% when 2 × 20 µCi and 1 × 40 µCi 30 weeks after starting of treatment due to significant hematological toxicity [71]. It was shown that combination of fractionated injection of [212Pb]Pb&#;DOTAMTATE (3 × 10 µCi) with 5-fluorouracil resulted in 79% of mice surviving vs. <50% for [212Pb]Pb&#;DOTAMTATE (3 × 10 µCi) alone after a 31-week period. It was caused by an effective slowdown of tumor growth without full depression because, at the beginning of therapy, the tumor achieved a significant size of 100&#;300 mm3.
Moreover, regarding the successful application of alpha-emitting 225Ac and 213Bi for the treatment of prostate cancer [101], PSMA ligand was also conjugated with DOTAM (TCMC) [18,80] and tested in vivo with 212Pb on xenografted models. Consequent elaboration of conjugates of PSMA-inhibiting moiety with TCMC was performed specifically for 212Pb [18,71,80,102]. The well-tolerated dose of 9 µCi (330 kBq), in agreement with the above-mentioned values, was shown to demonstrate survival elongation, inhibition of tumor growth, and the same therapeutic index as PSMA-617 labeled by 225Ac (0.5&#;2.7 µCi, &#; Bq) or 177Lu (54&#; µCi, 200 kBq&#;11.1 MBq) [18]. This is due to the high dose rate delivered to the malignancy by 212Pb because of the lower half-life and correspondence of biological half-life of labeled conjugate and physical half-life of radionuclide.
In order to evaluate the role of the internalizing character of a targeting moiety, alpha radiation&#;s effectiveness was tested for small volume (10 mm3) peritoneal carcinomatosis [96,103] with two types of mAbs 35A7 (non-internalizing) and trastuzumab (internalizing). It was shown that, upon the injection of 40 µCi ( kBq), hematological toxicity appeared, while no renal or hepatic influence was detected. This value was crucial for bone marrow and kidneys with other mAbs in the aforementioned papers [65,75]. It is possible that, in addition to mAb replacement, immunoconjugates studied in [103] were prepared with TCMC instead of DOTA, which prevented dissociation and respective irradiation of dose-limiting organs. As a result, [212Pb]Pb&#;trastuzumab caused a higher increase in median survival for non-treated compared to [212Pb]Pb&#;35A7 despite a lower dose absorbed [96,103] from 18 d to >125 d vs. 94 d. This can be a sequence of synergistic interaction of trastuzumab itself accompanied by alpha-radiation, although individually trastuzumab did not affect this tumor [96].
Trastuzumab, labeled with 212Pb, was assessed for the treatment of prostate cancer [23,66]. In contrast to I.P. injection for abdominal cancer treatment [68,94,95], these experiments were performed using an intravenous (I.V.) injection of [212Pb]Pb&#;TCMC&#;trastuzumab. Neither hematological, histological, liver, or kidney toxicity nor significant weight loss in the time period of 21 days after treatment was observed [66]. However, biodistribution in 30 min at 3 days showed that spleen, liver, and kidney retained a surprisingly high percentage of ID [23]. This appears to correlate with moderate curative ability; the median survival was lengthened from 47 to 61 days with 20 µCi (740 kBq) of 212Pb [66]. This modest response could be caused by the low expression of HER2+ receptors by this cell line [66], leading to the long circulation of labeled antibodies in the blood pool and accumulation in organs with large blood supply [23]. On the other hand, low expression of specific receptors towards trastuzumab was supposed to be effective for treatment by alpha-radiation [68], but obviously, it depends on how low the expression is.
Besides trastuzumab, recently, 212Pb was demonstrated to be effective in preclinical studies for the treatment by labeled antibodies of multiple myeloma [72], non-Hodgkin lymphoma [104], ovarian cancer [105], and pancreatic adenocarcinoma [26].
Targeted therapy with 212Pb was also evaluated for the treatment of brain metastases [36,106]. Due to the blood&#;brain barrier, application of the suggested anti-VCAM1 (vascular cell adhesion molecule 1) antibody assumes irradiation of early brain metastases in the vicinity of vessels (depth ~50 µm), lacking the necessity to penetrate through the vessel wall. Starting from modeling by the Monte Carlo technique, it was shown that emission of 212Pb with two highly energetic alpha-particles in the decay chain could provide a high yield of double-strand breaks per decay in the 40&#;100 µm range [106,107]. The feasibility of this approach was experimentally approved for mice with brain metastases from breast cancer. The therapeutic effect and significant increase in overall survival along with lack of liver and blood toxicity were demonstrated [36]. Moreover, increased expression of the corresponding receptors was observed after external irradiation therapy causing enhancement of the effectiveness of [212Pb]Pb&#;VCAM1 treatment following the external irradiation.
Another approach for specific delivery of radioactivity can be the pretargeting technique when malignancies or other organs of interest are bound with an affine molecule that does not contain radioactivity. This process of binding pretargeting compounds with affected tissue can take a prolonged time. Then, labeled by radionuclide specific molecule is injected and quickly accumulates in the areas with the pretargeting units. This method was already tested with [212Pb]Pb&#;DOTA&#;biotin and streptavidin as the pretargeting molecule [76]. It was shown that upon injection of 10 µCi (360 kBq) in xenografted mice, high tumor/marrow and tumor/kidney ratios were observed, while in healthy mice, radioactivity cleared quickly. The latter proved the applicability of this concept, especially for 212Pb/212Bi, regarding their high bone marrow and kidney toxicity.
In addition to biomolecules and their synthetic analogs and derivatives, low molecular weight compounds bearing affinity to specific organs can be used for target delivery. Phosphonate derivatives of EDTMP and DOTMP [86] were tested for addressing radionuclides to tissues with an increased phosphorus intake upon the growth of bone malignancies. The [212Pb]Pb&#;DOTMP was shown to be quickly cleared from the blood pool and accumulated in bones in the frame of searching alpha-emitting alternative for radiopharmaceutical [153Sm]Sm-EDTMP [86] was used for therapy of bone malignancies and metastases. Furthermore, the application of 224Ra for the treatment of skeletal metastases and peritoneal malignancies is hindered by the uncertain fate of the relatively long-lived progeny radionuclide 212Pb [108,109]. According to its affinity towards EDTMP, this ligand can be added to applied solution or suspension to provide fast chelation of the released 212Pb. In the case of the 224Ra chloride salt solution, 212Pb chelated by phosphonate is returned to bone metastases for treatment along with 224Ra [109].
According to most preclinical studies discussed above, one of the main questions is the dose of 212Pb that can be safely used for therapy. That is why before clinical trials [212Pb], Pb&#;TCMC&#;trastuzumab was assessed in monkeys as soon as they had similar to human expression of Her2+ receptors [21]. Interestingly non-eo was found in the ratio of activities, 212Pb/212Bi = 1.1&#;1.5, on the first time points, which could be due to the loss of bismuth from the peritoneal cavity or caused by the inequality in the detection of 236 keV (212Pb) and 738 keV (212Bi) by the gamma camera. This did not affect any serious toxicity; no adverse effects except slight to bone marrow were observed. Even for bone marrow, no damage was detected upon microscopic evaluation of its cells. The lack of toxicity was promising since, for human experiments, twice lower doses of radioactivity were suggested [110,111].
Besides the direct empirical finding of tolerated doses in mice and other organisms, compounds labeled with 203Pb and SPECT can be used as a surrogate for 212Pb in some labeled peptides [19]. In order to evaluate the dosimetry of [212Pb]Pb&#;TCMC&#;PSMA, this ligand was labeled with 203Pb and tested by SPECT in patients accompanied by phantom application and calculations [71]. However, in this case, the biodistribution of radioactivity in the case of 203Pb cannot be simply translated for 212Pb compounds due to peculiarities of the latter&#;s decay, making the fate of daughter radionuclide 212Bi uncertain [77].
Additionally, it was shown that despite many daughter radionuclides and their emission, quantitative SPECT of 212Pb itself is possible [112]. The latter opens up prospects of theranostic application, dosimetric estimation, and evaluation of treatment feasibility by 212Pb radiopharmaceuticals in each case.
This article is about the chemical element. For other uses, see Sulfur (disambiguation)
Sulfur (also spelled sulphur in British English) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with the chemical formula S8. Elemental sulfur is a bright yellow, crystalline solid at room temperature.
Sulfur is the tenth most abundant element by mass in the universe and the fifth most common on Earth. Though sometimes found in pure, native form, sulfur on Earth usually occurs as sulfide and sulfate minerals. Being abundant in native form, sulfur was known in ancient times, being mentioned for its uses in ancient India, ancient Greece, China, and ancient Egypt. Historically and in literature sulfur is also called brimstone,[7] which means "burning stone".[8] Today, almost all elemental sulfur is produced as a byproduct of removing sulfur-containing contaminants from natural gas and petroleum.[9][10] The greatest commercial use of the element is the production of sulfuric acid for sulfate and phosphate fertilizers, and other chemical processes. Sulfur is used in matches, insecticides, and fungicides. Many sulfur compounds are odoriferous, and the smells of odorized natural gas, skunk scent, bad breath, grapefruit, and garlic are due to organosulfur compounds. Hydrogen sulfide gives the characteristic odor to rotting eggs and other biological processes.
Sulfur is an essential element for all life, almost always in the form of organosulfur compounds or metal sulfides. Amino acids (two proteinogenic: cysteine and methionine, and many other non-coded: cystine, taurine, etc.) and two vitamins (biotin and thiamine) are organosulfur compounds crucial for life. Many cofactors also contain sulfur, including glutathione, and iron&#;sulfur proteins. Disulfides, S&#;S bonds, confer mechanical strength and insolubility of the (among others) protein keratin, found in outer skin, hair, and feathers. Sulfur is one of the core chemical elements needed for biochemical functioning and is an elemental macronutrient for all living organisms.
[
edit
]
[
edit
]
As a solid, sulfur is a characteristic lemon yellow; when burned, sulfur melts into a blood-red liquid and emits a blue flame.Sulfur forms several polyatomic molecules. The best-known allotrope is octasulfur, cyclo-S8. The point group of cyclo-S8 is D4d and its dipole moment is 0 D.[11] Octasulfur is a soft, bright-yellow solid that is odorless.[a] It melts at 115.21 °C (239.38 °F),[b] boils at 444.6 °C (832.3 °F).[7] At 95.2 °C (203.4 °F), below its melting temperature, cyclo-octasulfur begins slow changing from α-octasulfur to the β-polymorph.[13] The structure of the S8 ring is virtually unchanged by this phase change, which affects the intermolecular interactions. Cooling of molten sulfur gives freezing point in 119.6 °C (247.3 °F),[14] as it predominantly consists of the β-S8 molecules.[c] Between its melting and boiling temperatures, octasulfur changes its allotrope again, turning from β-octasulfur to γ-sulfur, again accompanied by a lower density but increased viscosity due to the formation of polymers.[13] At higher temperatures, the viscosity decreases as depolymerization occurs. Molten sulfur assumes a dark red color above 200 °C (392 °F). The density of sulfur is about 2 g/cm3, depending on the allotrope; all of the stable allotropes are excellent electrical insulators.
Sulfur sublimes more or less between 20 °C (68 °F) and 50 °C (122 °F).[18]
Sulfur is insoluble in water but soluble in carbon disulfide and, to a lesser extent, in other nonpolar organic solvents, such as benzene and toluene.
[
edit
]
Under normal conditions, sulfur hydrolyzes very slowly to mainly form hydrogen sulfide and sulfuric acid:
1
&#;2
S
8
H
2
H
2
H
2
4
Left: Liquid hydrogen sulfide inside a test tube. Right: A bottle of sulfuric acid.
The reaction involves adsorption of protons onto S
8 clusters, followed by disproportionation into the reaction products.[19]
The second, fourth and sixth ionization energies of sulfur are kJ/mol, kJ/mol and .8 kJ/mol, respectively. A composition of products of sulfur's reactions with oxidants (and its oxidation state) depends on that whether releasing out of a reaction energy overcomes these thresholds. Applying catalysts and / or supply of outer energy may vary sulfur's oxidation state and a composition of reaction products. While reaction between sulfur and oxygen at normal conditions gives sulfur dioxide (oxidation state +4), formation of sulfur trioxide (oxidation state +6) requires temperature 400&#;600 °C (750&#;1,100 °F) and presence of a catalyst.
In reactions with elements of lesser electronegativity, it reacts as an oxidant and forms sulfides, where it has oxidation state &#;2.
Sulfur reacts with nearly all other elements with the exception of the noble gases, even with the notoriously unreactive metal iridium (yielding iridium disulfide).[20] Some of those reactions need elevated temperatures.[21]
[
edit
]
The structure of the cyclooctasulfur molecule, S8Sulfur forms over 30 solid allotropes, more than any other element.[22] Besides S8, several other rings are known.[23] Removing one atom from the crown gives S7, which is of a deeper yellow than S8. HPLC analysis of "elemental sulfur" reveals an equilibrium mixture of mainly S8, but with S7 and small amounts of S6.[24] Larger rings have been prepared, including S12 and S18.[25][26]
Amorphous or "plastic" sulfur is produced by rapid cooling of molten sulfur&#;for example, by pouring it into cold water. X-ray crystallography studies show that the amorphous form may have a helical structure with eight atoms per turn. The long coiled polymeric molecules make the brownish substance elastic, and in bulk this form has the feel of crude rubber. This form is metastable at room temperature and gradually reverts to the crystalline molecular allotrope, which is no longer elastic. This process happens within a matter of hours to days, but can be rapidly catalyzed.
[
edit
]
Sulfur has 23 known isotopes, four of which are stable: 32S (94.99%±0.26%), 33S (0.75%±0.02%), 34S (4.25%±0.24%), and 36S (0.01%±0.01%).[27][28] Other than 35S, with a half-life of 87 days, the radioactive isotopes of sulfur have half-lives less than 3 hours.
The preponderance of 32S is explained by its production in the so-called alpha-process (one of the main classes of nuclear fusion reactions) in exploding stars. Other stable sulfur isotopes are produced in the bypass processes related with 34Ar, and their composition depends on a type of a stellar explosion. For example, proportionally more 33S comes from novae than from supernovae.[29]
On the planet Earth the sulfur isotopic composition was determined by the Sun. Though it is assumed that the distribution of different sulfur isotopes should be more or less equal, it has been found that proportions of two most abundant sulfur isotopes 32S and 34S varies in different samples. Assaying of these isotopes ratio (δ34S) in the samples allows to make suggestions about their chemical history, and with support of other methods, it allows to age-date the samples, estimate temperature of equilibrium between ore and water, determine pH and oxygen fugacity, identify the activity of sulfate-reducing bacteria in the time of formation of the sample, or suggest the main sources of sulfur in ecosystems.[30] However, there are ongoing discussions about what is the real reason of the δ34S shifts, biological activity or postdeposital alteration.[31]
For example, when sulfide minerals are precipitated, isotopic equilibration among solids and liquid may cause small differences in the δ34S values of co-genetic minerals. The differences between minerals can be used to estimate the temperature of equilibration. The δ13C and δ34S of coexisting carbonate minerals and sulfides can be used to determine the pH and oxygen fugacity of the ore-bearing fluid during ore formation.
Scientists measure the sulfur isotopes of minerals in rocks and sediments to study the redox conditions in the oceans in the past. Sulfate-reducing bacteria in marine sediment fractionate sulfur isotopes as they take in sulfate and produce sulfide. Prior to the s, it was thought that sulfate reduction could fractionate sulfur isotopes up to 46 permil[32] and fractionation larger than 46 permil recorded in sediments must be due to disproportionation of sulfur compounds in the sediment. This view has changed since the s as experiments show that sulfate-reducing bacteria can fractionate to 66 permil.[33] As substrates for disproportionation are limited by the product of sulfate reduction, the isotopic effect of disproportionation should be less than 16 permil in most sedimentary settings.[34]
In most forest ecosystems, sulfate is derived mostly from the atmosphere; weathering of ore minerals and evaporites contribute some sulfur. Sulfur with a distinctive isotopic composition has been used to identify pollution sources, and enriched sulfur has been added as a tracer in hydrologic studies. Differences in the natural abundances can be used in systems where there is sufficient variation in the 34S of ecosystem components. Rocky Mountain lakes thought to be dominated by atmospheric sources of sulfate have been found to have measurably different 34S values than lakes believed to be dominated by watershed sources of sulfate.
The radioactive 35S is formed in cosmic ray spallation of the atmospheric 40Ar. This fact may be used for proving the presence of recent (not more than 1 year) atmospheric sediments in various things. This isotope may be obtained artificially by different ways. In practice, the reaction 35Cl + n &#; 35S + p is used by irradiating potassium chloride with neutrons.[35] The isotope 35S is used in various sulfur-containing compounds as a radioactive tracer for many biological studies, for example, the Hershey-Chase experiment.
Because of the weak beta activity of 35S, its compounds are relatively safe as long as they are not ingested or absorbed by the body.[36]
[
edit
]
Sulfur vat from which railroad cars are loaded, Freeport Sulphur Co., Hoskins Mound, Texas () Most of the yellow and orange hues of Io are due to elemental sulfur and sulfur compounds deposited by active volcanoes. Sulfur extraction, East Java A man carrying sulfur blocks from Kawah Ijen, a volcano in East Java, Indonesia,32S is created inside massive stars, at a depth where the temperature exceeds 2.5×109 K, by the fusion of one nucleus of silicon plus one nucleus of helium.[37] As this nuclear reaction is part of the alpha process that produces elements in abundance, sulfur is the 10th most common element in the universe.
Sulfur, usually as sulfide, is present in many types of meteorites. Ordinary chondrites contain on average 2.1% sulfur, and carbonaceous chondrites may contain as much as 6.6%. It is normally present as troilite (FeS), but there are exceptions, with carbonaceous chondrites containing free sulfur, sulfates and other sulfur compounds.[38] The distinctive colors of Jupiter's volcanic moon Io are attributed to various forms of molten, solid, and gaseous sulfur.[39] In July , elemental sulfur was confirmed to exist on Mars by surprise, after the Curiosity rover ran over and crushed a rock revealing sulfur crystals inside it.[40]
Sulfur is the fifth most common element by mass in the Earth. Elemental sulfur can be found near hot springs and volcanic regions in many parts of the world, especially along the Pacific Ring of Fire; such volcanic deposits are currently mined in Indonesia, Chile, and Japan. These deposits are polycrystalline, with the largest documented single crystal measuring 22 cm × 16 cm × 11 cm (8.7 in × 6.3 in × 4.3 in).[41] Historically, Sicily was a major source of sulfur in the Industrial Revolution.[42] Lakes of molten sulfur up to about 200 m (660 ft) in diameter have been found on the sea floor, associated with submarine volcanoes, at depths where the boiling point of water is higher than the melting point of sulfur.[43]
Native sulfur is synthesized by anaerobic bacteria acting on sulfate minerals such as gypsum in salt domes.[44][45] Significant deposits in salt domes occur along the coast of the Gulf of Mexico, and in evaporites in eastern Europe and western Asia. Native sulfur may be produced by geological processes alone. Fossil-based sulfur deposits from salt domes were once the basis for commercial production in the United States, Russia, Turkmenistan, and Ukraine.[46] Currently, commercial production is still carried out in the Osiek mine in Poland. Such sources are now of secondary commercial importance, and most are no longer worked.
Common naturally occurring sulfur compounds include the sulfide minerals, such as pyrite (iron sulfide), cinnabar (mercury sulfide), galena (lead sulfide), sphalerite (zinc sulfide), and stibnite (antimony sulfide); and the sulfate minerals, such as gypsum (calcium sulfate), alunite (potassium aluminium sulfate), and barite (barium sulfate). On Earth, just as upon Jupiter's moon Io, elemental sulfur occurs naturally in volcanic emissions, including emissions from hydrothermal vents.
The main industrial source of sulfur is now petroleum and natural gas.[9]
[
edit
]
Common oxidation states of sulfur range from &#;2 to +6. Sulfur forms stable compounds with all elements except the noble gases.
[
edit
]
Lapis lazuli owes its blue color to a trisulfur radical anion (S
&#;
3
Sulfur polycations, S2+8, S2+4 and S2+16 are produced when sulfur is reacted with oxidizing agents in a strongly acidic solution.[47] The colored solutions produced by dissolving sulfur in oleum were first reported as early as by C. F. Bucholz, but the cause of the color and the structure of the polycations involved was only determined in the late s. S2+8 is deep blue, S2+4 is yellow and S2+16 is red.[13]
Reduction of sulfur gives various polysulfides with the formula S2&#;
x, many of which have been obtained in crystalline form. Illustrative is the production of sodium tetrasulfide:
4 Na + S8 &#; 2 Na2S4
Some of these dianions dissociate to give radical anions, such as S&#;3 gives the blue color of the rock lapis lazuli.
Two parallel sulfur chains grown inside a single-wall carbon nanotube (CNT, a). Zig-zag (b) and straight (c) S chains inside double-wall CNTs[
48]
This reaction highlights a distinctive property of sulfur: its ability to catenate (bind to itself by formation of chains). Protonation of these polysulfide anions produces the polysulfanes, H2Sx, where x = 2, 3, and 4.[49] Ultimately, reduction of sulfur produces sulfide salts:
16 Na + S8 &#; 8 Na2S
The interconversion of these species is exploited in the sodium&#;sulfur battery.
[
edit
]
Treatment of sulfur with hydrogen gives hydrogen sulfide. When dissolved in water, hydrogen sulfide is mildly acidic:[7]
H2S &#; HS&#; + H+
Hydrogen sulfide gas and the hydrosulfide anion are extremely toxic to mammals, due to their inhibition of the oxygen-carrying capacity of hemoglobin and certain cytochromes in a manner analogous to cyanide and azide (see below, under precautions).
[
edit
]
The two principal sulfur oxides are obtained by burning sulfur:
2 &#; SO2 (sulfur dioxide)S + O&#; SO
2 + O2 &#; 2 SO3 (sulfur trioxide)2 SO+ O&#; 2 SO
Many other sulfur oxides are observed including the sulfur-rich oxides include sulfur monoxide, disulfur monoxide, disulfur dioxides, and higher oxides containing peroxo groups.
[
edit
]
Sulfur reacts with fluorine to give the highly reactive sulfur tetrafluoride and the highly inert sulfur hexafluoride.[50] Whereas fluorine gives S(IV) and S(VI) compounds, chlorine gives S(II) and S(I) derivatives. Thus, sulfur dichloride, disulfur dichloride, and higher chlorosulfanes arise from the chlorination of sulfur. Sulfuryl chloride and chlorosulfuric acid are derivatives of sulfuric acid; thionyl chloride (SOCl2) is a common reagent in organic synthesis.[51] Bromine also oxidizes sulfur to form sulfur dibromide and disulfur dibromide.[51]
[
edit
]
Sulfur oxidizes cyanide and sulfite to give thiocyanate and thiosulfate, respectively.
[
edit
]
Sulfur reacts with many metals. Electropositive metals give polysulfide salts. Copper, zinc, and silver are attacked by sulfur; see tarnishing. Although many metal sulfides are known, most are prepared by high temperature reactions of the elements.[52] Geoscientists also study the isotopes of metal sulfides in rocks and sediment to study environmental conditions in the Earth's past.[53]
[
edit
]
Some of the main classes of sulfur-containing organic compounds include the following:[54]
Compounds with carbon&#;sulfur multiple bonds are uncommon, an exception being carbon disulfide, a volatile colorless liquid that is structurally similar to carbon dioxide. It is used as a reagent to make the polymer rayon and many organosulfur compounds. Unlike carbon monoxide, carbon monosulfide is stable only as an extremely dilute gas, found between solar systems.[55]
Organosulfur compounds are responsible for some of the unpleasant odors of decaying organic matter. They are widely known as the odorant in domestic natural gas, garlic odor, and skunk spray, as well as a component of bad breath odor. Not all organic sulfur compounds smell unpleasant at all concentrations: the sulfur-containing monoterpenoid grapefruit mercaptan in small concentrations is the characteristic scent of grapefruit, but has a generic thiol odor at larger concentrations. Sulfur mustard, a potent vesicant, was used in World War I as a disabling agent.[56]
Sulfur&#;sulfur bonds are a structural component used to stiffen rubber, similar to the disulfide bridges that rigidify proteins (see biological below). In the most common type of industrial "curing" or hardening and strengthening of natural rubber, elemental sulfur is heated with the rubber to the point that chemical reactions form disulfide bridges between isoprene units of the polymer. This process, patented in ,[citation needed] made rubber a major industrial product, especially in automobile tires. Because of the heat and sulfur, the process was named vulcanization, after the Roman god of the forge and volcanism.
[
edit
]
[
edit
]
Pharmaceutical container for sulfur from the first half of the 20th century. From the Museo del Objeto del Objeto collectionBeing abundantly available in native form, sulfur was known in ancient times and is referred to in the Torah (Genesis). English translations of the Christian Bible commonly referred to burning sulfur as "brimstone", giving rise to the term "fire-and-brimstone" sermons, in which listeners are reminded of the fate of eternal damnation that await the unbelieving and unrepentant. It is from this part of the Bible[57] that Hell is implied to "smell of sulfur" (likely due to its association with volcanic activity). According to the Ebers Papyrus, a sulfur ointment was used in ancient Egypt to treat granular eyelids. Sulfur was used for fumigation in preclassical Greece;[58] this is mentioned in the Odyssey.[59] Pliny the Elder discusses sulfur in book 35 of his Natural History, saying that its best-known source is the island of Melos. He mentions its use for fumigation, medicine, and bleaching cloth.[60]
A natural form of sulfur known as shiliuhuang (&#;&#;&#;) was known in China since the 6th century BC and found in Hanzhong.[61] By the 3rd century, the Chinese had discovered that sulfur could be extracted from pyrite.[61] Chinese Daoists were interested in sulfur's flammability and its reactivity with certain metals, yet its earliest practical uses were found in traditional Chinese medicine.[61] The Wujing Zongyao of AD described various formulas for Chinese black powder, which is a mixture of potassium nitrate (KNO
3), charcoal, and sulfur.[62]
Indian alchemists, practitioners of the "science of chemicals" (Sanskrit: &#;&#;&#;&#;&#;&#;&#;&#;&#;, romanized: rasaśāstra), wrote extensively about the use of sulfur in alchemical operations with mercury, from the eighth century AD onwards.[64] In the rasaśāstra tradition, sulfur is called "the smelly" (&#;&#;&#;&#;&#;, gandhaka).
The company is the world’s best radium salt powder in bulk supplier. We are your one-stop shop for all needs. Our staff are highly-specialized and will help you find the product you need.
Early European alchemists gave sulfur a unique alchemical symbol, a triangle atop a cross (&#;). (This is sometimes confused with the astronomical crossed-spear symbol &#; for 2 Pallas.) The variation known as brimstone has a symbol combining a two-barred cross atop a lemniscate (&#;). In traditional skin treatment, elemental sulfur was used (mainly in creams) to alleviate such conditions as scabies, ringworm, psoriasis, eczema, and acne. The mechanism of action is unknown&#;though elemental sulfur does oxidize slowly to sulfurous acid, which is (through the action of sulfite) a mild reducing and antibacterial agent.[65][66][67]
[
edit
]
Today sulfur is known to have antifungal, antibacterial, and keratolytic activity; in the past it was used against acne vulgaris, rosacea, seborrheic dermatitis, dandruff, pityriasis versicolor, scabies, and warts.[
68]
This advertisement baselessly claims efficacy against rheumatism, gout, baldness, and graying of hair.Sulfur appears in a column of fixed (non-acidic) alkali in a chemical table of .[69] Antoine Lavoisier used sulfur in combustion experiments, writing of some of these in .[70]
Sulfur deposits in Sicily were the dominant source for more than a century. By the late 18th century, about 2,000 tonnes per year of sulfur were imported into Marseille, France, for the production of sulfuric acid for use in the Leblanc process. In industrializing Britain, with the repeal of tariffs on salt in , demand for sulfur from Sicily surged upward. The increasing British control and exploitation of the mining, refining, and transportation of the sulfur, coupled with the failure of this lucrative export to transform Sicily's backward and impoverished economy, led to the Sulfur Crisis of , when King Ferdinand II gave a monopoly of the sulfur industry to a French firm, violating an earlier trade agreement with Britain. A peaceful solution was eventually negotiated by France.[71][72]
In , elemental sulfur was discovered in underground deposits in Louisiana and Texas. The highly successful Frasch process was developed to extract this resource.[73]
In the late 18th century, furniture makers used molten sulfur to produce decorative inlays.[74] Molten sulfur is sometimes still used for setting steel bolts into drilled concrete holes where high shock resistance is desired for floor-mounted equipment attachment points. Pure powdered sulfur was used as a medicinal tonic and laxative.[46]
With the advent of the contact process, the majority of sulfur today is used to make sulfuric acid for a wide range of uses, particularly fertilizer.[75]
In recent times, the main source of sulfur has become petroleum and natural gas. This is due to the requirement to remove sulfur from fuels in order to prevent acid rain, and has resulted in a surplus of sulfur.[9]
[
edit
]
Sulfur is derived from the Latin word sulpur, which was Hellenized to sulphur in the erroneous belief that the Latin word came from Greek. This spelling was later reinterpreted as representing an /f/ sound and resulted in the spelling sulfur, which appears in Latin toward the end of the Classical period. The true Ancient Greek word for sulfur, θε&#;ον, theîon (from earlier θέειον, théeion), is the source of the international chemical prefix thio-. The Modern Standard Greek word for sulfur is θείο, theío.
In 12th-century Anglo-French, it was sulfre. In the 14th century, the erroneously Hellenized Latin -ph- was restored in Middle English sulphre. By the 15th century, both full Latin spelling variants sulfur and sulphur became common in English. The parallel f~ph spellings continued in Britain until the 19th century, when the word was standardized as sulphur.[76] On the other hand, sulfur was the form chosen in the United States, whereas Canada uses both.
The IUPAC adopted the spelling sulfur in [77][78] as did the Nomenclature Committee of the Royal Society of Chemistry in , restoring the spelling sulfur to Britain.[79] Oxford Dictionaries note that "in chemistry and other technical uses ... the -f- spelling is now the standard form for this and related words in British as well as US contexts, and is increasingly used in general contexts as well."[80]
[
edit
]
Sicilian kiln used to obtain sulfur from volcanic rock (diagram from a chemistry book) Traditional sulfur mining at Ijen Volcano, East Java, Indonesia. This image shows the dangerous and rugged conditions the miners face, including toxic smoke and high drops, as well as their lack of protective equipment. The pipes over which they are standing are for condensing sulfur vapors.Sulfur may be found by itself and historically was usually obtained in this form; pyrite has also been a source of sulfur.[81] In volcanic regions in Sicily, in ancient times, it was found on the surface of the Earth, and the "Sicilian process" was used: sulfur deposits were piled and stacked in brick kilns built on sloping hillsides, with airspaces between them. Then, some sulfur was pulverized, spread over the stacked ore and ignited, causing the free sulfur to melt down the hills. Eventually the surface-borne deposits played out, and miners excavated veins that ultimately dotted the Sicilian landscape with labyrinthine mines. Mining was unmechanized and labor-intensive, with pickmen freeing the ore from the rock, and mine-boys or carusi carrying baskets of ore to the surface, often through a mile or more of tunnels. Once the ore was at the surface, it was reduced and extracted in smelting ovens. The conditions in Sicilian sulfur mines were horrific, prompting Booker T. Washington to write "I am not prepared just now to say to what extent I believe in a physical hell in the next world, but a sulfur mine in Sicily is about the nearest thing to hell that I expect to see in this life."[82] Sulfur is still mined from surface deposits in poorer nations with volcanoes, such as Indonesia, and worker conditions have not improved much since Booker T. Washington's days.[83]
Elemental sulfur was extracted from salt domes (in which it sometimes occurs in nearly pure form) until the late 20th century. Sulfur is now produced as a side product of other industrial processes such as in oil refining, in which sulfur is undesired. As a mineral, native sulfur under salt domes is thought to be a fossil mineral resource, produced by the action of anaerobic bacteria on sulfate deposits. It was removed from such salt-dome mines mainly by the Frasch process.[46] In this method, superheated water was pumped into a native sulfur deposit to melt the sulfur, and then compressed air returned the 99.5% pure melted product to the surface. Throughout the 20th century this procedure produced elemental sulfur that required no further purification. Due to a limited number of such sulfur deposits and the high cost of working them, this process for mining sulfur has not been employed in a major way anywhere in the world since .[84][85]
Sulfur recovered from hydrocarbons in Alberta, stockpiled for shipment in North Vancouver, British ColumbiaToday, sulfur is produced from petroleum, natural gas, and related fossil resources, from which it is obtained mainly as hydrogen sulfide.[9] Organosulfur compounds, undesirable impurities in petroleum, may be upgraded by subjecting them to hydrodesulfurization, which cleaves the C&#;S bonds:[84][85]
R-S-R + 2 H2 &#; 2 RH + H2S
The resulting hydrogen sulfide from this process, and also as it occurs in natural gas, is converted into elemental sulfur by the Claus process. This process entails oxidation of some hydrogen sulfide to sulfur dioxide and then the comproportionation of the two:[84][85]
3 O2 + 2 H2S &#; 2 SO2 + 2 H2O
SO2 + 2 H2S &#; 3 S + 2 H2O
Production and price (US market) of elemental sulfurOwing to the high sulfur content of the Athabasca Oil Sands, stockpiles of elemental sulfur from this process now exist throughout Alberta, Canada.[86] Another way of storing sulfur is as a binder for concrete, the resulting product having some desirable properties (see sulfur concrete).[87]
The world production of sulfur in amounted to 69 million tonnes (Mt), with more than 15 countries contributing more than 1 Mt each. Countries producing more than 5 Mt are China (9.6), the United States (8.8), Canada (7.1) and Russia (7.1).[88] Production has been slowly increasing from to ; the price was unstable in the s and around .[89]
[
edit
]
[
edit
]
Elemental sulfur is used mainly as a precursor to other chemicals. Approximately 85% () is converted to sulfuric acid (H2SO4):
1
&#;8
S8
+3
&#;2
O2
+H2O
&#;H2SO4
Sulfuric acid production inIn , the United States produced more sulfuric acid than any other inorganic industrial chemical.[89] The principal use for the acid is the extraction of phosphate ores for the production of fertilizer manufacturing. Other applications of sulfuric acid include oil refining, wastewater processing, and mineral extraction.[46]
[
edit
]
Sulfur reacts directly with methane to give carbon disulfide, which is used to manufacture cellophane and rayon.[46] One of the uses of elemental sulfur is in vulcanization of rubber, where polysulfide chains crosslink organic polymers. Large quantities of sulfites are used to bleach paper and to preserve dried fruit. Many surfactants and detergents (e.g. sodium lauryl sulfate) are sulfate derivatives. Calcium sulfate, gypsum (CaSO4·2H2O) is mined on the scale of 100 million tonnes each year for use in Portland cement and fertilizers.
When silver-based photography was widespread, sodium and ammonium thiosulfate were widely used as "fixing agents". Sulfur is a component of gunpowder ("black powder").
[
edit
]
Amino acids synthesized by living organisms such as methionine and cysteine contain organosulfur groups (thioester and thiol respectively). The antioxidant glutathione protecting many living organisms against free radicals and oxidative stress also contains organic sulfur. Some crops such as onion and garlic also produce different organosulfur compounds such as syn-propanethial-S-oxide responsible of lacrymal irritation (onions), or diallyl disulfide and allicin (garlic). Sulfates, commonly found in soils and groundwaters are often a sufficient natural source of sulfur for plants and bacteria. Atmospheric deposition of sulfur dioxide (SO2) is also a common artificial source (coal combustion) of sulfur for the soils. Under normal circumstances, in most agricultural soils, sulfur is not a limiting nutrient for plants and microorganisms (see Liebig's barrel). However, in some circumstances, soils can be depleted in sulfate, e.g. if this later is leached by meteoric water (rain) or if the requirements in sulfur for some types of crops are high. This explains that sulfur is increasingly recognized and used as a component of fertilizers. The most important form of sulfur for fertilizer is calcium sulfate, commonly found in nature as the mineral gypsum (CaSO4·2H2O). Elemental sulfur is hydrophobic (not soluble in water) and cannot be used directly by plants. Elemental sulfur (ES) is sometimes mixed with bentonite to amend depleted soils for crops with high requirement in organo-sulfur. Over time, oxidation abiotic processes with atmospheric oxygen and soil bacteria can oxidize and convert elemental sulfur to soluble derivatives, which can then be used by microorganisms and plants. Sulfur improves the efficiency of other essential plant nutrients, particularly nitrogen and phosphorus.[90] Biologically produced sulfur particles are naturally hydrophilic due to a biopolymer coating and are easier to disperse over the land in a spray of diluted slurry, resulting in a faster uptake by plants.
The plants requirement for sulfur equals or exceeds the requirement for phosphorus. It is an essential nutrient for plant growth, root nodule formation of legumes, and immunity and defense systems. Sulfur deficiency has become widespread in many countries in Europe.[91][92][93] Because atmospheric inputs of sulfur continue to decrease, the deficit in the sulfur input/output is likely to increase unless sulfur fertilizers are used. Atmospheric inputs of sulfur decrease because of actions taken to limit acid rains.[94][90]
[
edit
]
Sulfur candle originally sold for home fumigationElemental sulfur is one of the oldest fungicides and pesticides. "Dusting sulfur", elemental sulfur in powdered form, is a common fungicide for grapes, strawberry, many vegetables and several other crops. It has a good efficacy against a wide range of powdery mildew diseases as well as black spot. In organic production, sulfur is the most important fungicide. It is the only fungicide used in organically farmed apple production against the main disease apple scab under colder conditions. Biosulfur (biologically produced elemental sulfur with hydrophilic characteristics) can also be used for these applications.
Standard-formulation dusting sulfur is applied to crops with a sulfur duster or from a dusting plane. Wettable sulfur is the commercial name for dusting sulfur formulated with additional ingredients to make it water miscible.[87][95] It has similar applications and is used as a fungicide against mildew and other mold-related problems with plants and soil.
Elemental sulfur powder is used as an "organic" (i.e., "green") insecticide (actually an acaricide) against ticks and mites. A common method of application is dusting the clothing or limbs with sulfur powder.
A diluted solution of lime sulfur (made by combining calcium hydroxide with elemental sulfur in water) is used as a dip for pets to destroy ringworm (fungus), mange, and other dermatoses and parasites.
Sulfur candles of almost pure sulfur were burned to fumigate structures and wine barrels, but are now considered too toxic for residences.
[
edit
]
Sulfur (specifically octasulfur, S8) is used in pharmaceutical skin preparations for the treatment of acne and other conditions. It acts as a keratolytic agent and also kills bacteria, fungi, scabies mites, and other parasites.[96] Precipitated sulfur and colloidal sulfur are used, in form of lotions, creams, powders, soaps, and bath additives, for the treatment of acne vulgaris, acne rosacea, and seborrhoeic dermatitis.[97]
Many drugs contain sulfur.[98] Early examples include antibacterial sulfonamides, known as sulfa drugs. A more recent example is mucolytic acetylcysteine. Sulfur is a part of many bacterial defense molecules. Most β-lactam antibiotics, including the penicillins, cephalosporins and monobactams contain sulfur.[54]
[
edit
]
Due to their high energy density and the availability of sulfur, there is ongoing research in creating rechargeable lithium&#;sulfur batteries. Until now, carbonate electrolytes have caused failures in such batteries after a single cycle. In February , researchers at Drexel University have not only created a prototypical battery that lasted recharge cycles, but also found the first monoclinic gamma sulfur that remained stable below 95 degrees Celsius.[99]
[
edit
]
Sulfur is an essential component of all living cells. It is the eighth most abundant element in the human body by weight,[100] about equal in abundance to potassium, and slightly greater than sodium and chlorine.[101] A 70 kg (150 lb) human body contains about 140 grams (4.9 oz) of sulfur.[102] The main dietary source of sulfur for humans is sulfur-containing amino-acids,[103] which can be found in plant and animal proteins.[104]
[
edit
]
In the s, while studying Beggiatoa (a bacterium living in a sulfur rich environment), Sergei Winogradsky found that it oxidized hydrogen sulfide (H2S) as an energy source, forming intracellular sulfur droplets. Winogradsky referred to this form of metabolism as inorgoxidation (oxidation of inorganic compounds).[105] Another contributor, who continued to study it was Selman Waksman.[106] Primitive bacteria that live around deep ocean volcanic vents oxidize hydrogen sulfide for their nutrition, as discovered by Robert Ballard.[10]
Sulfur oxidizers can use as energy sources reduced sulfur compounds, including hydrogen sulfide, elemental sulfur, sulfite, thiosulfate, and various polythionates (e.g., tetrathionate).[107] They depend on enzymes such as sulfur oxygenase and sulfite oxidase to oxidize sulfur to sulfate. Some lithotrophs can even use the energy contained in sulfur compounds to produce sugars, a process known as chemosynthesis. Some bacteria and archaea use hydrogen sulfide in place of water as the electron donor in chemosynthesis, a process similar to photosynthesis that produces sugars and uses oxygen as the electron acceptor. Sulfur-based chemosynthesis may be simplifiedly compared with photosynthesis:
H2S + CO2 &#; sugars + S
H2O + CO2 &#; sugars + O2
There are bacteria combining these two ways of nutrition: green sulfur bacteria and purple sulfur bacteria.[108] Also sulfur-oxidizing bacteria can go into symbiosis with larger organisms, enabling the later to use hydrogen sulfide as food to be oxidized. Example: the giant tube worm.[109]
There are sulfate-reducing bacteria, that, by contrast, "breathe sulfate" instead of oxygen. They use organic compounds or molecular hydrogen as the energy source. They use sulfur as the electron acceptor, and reduce various oxidized sulfur compounds back into sulfide, often into hydrogen sulfide. They can grow on other partially oxidized sulfur compounds (e.g. thiosulfates, thionates, polysulfides, sulfites).
There are studies pointing that many deposits of native sulfur in places that were the bottom of the ancient oceans have biological origin.[110][111][112] These studies indicate that this native sulfur have been obtained through biological activity, but what is responsible for that (sulfur-oxidizing bacteria or sulfate-reducing bacteria) is still unknown for sure.
Sulfur is absorbed by plants roots from soil as sulfate and transported as a phosphate ester. Sulfate is reduced to sulfide via sulfite before it is incorporated into cysteine and other organosulfur compounds.[113]
SO
2&#;
4
&#;SO
2&#;
3
&#;H2S
&#; cysteine (thiol) &#; methionine (thioether)While the plants' role in transferring sulfur to animals by food chains is more or less understood, the role of sulfur bacteria is just getting investigated.[114][115]
[
edit
]
In all forms of life, most of the sulfur is contained in two proteinogenic amino acids (cysteine and methionine), thus the element is present in all proteins that contain these amino acids, as well as in respective peptides.[116] Some of the sulfur is comprised in certain metabolites&#;many of which are cofactors&#;and sulfated polysaccharides of connective tissue (chondroitin sulfates, heparin).
Schematic representation of disulfide bridges (in yellow) between two protein helicesProteins, to execute their biological function, need to have specific space geometry. Formation of this geometry is performed in a process called protein folding, and is provided by intra- and inter-molecular bonds. The process has several stages. While at premier stages a polypeptide chain folds due to hydrogen bonds, at later stages folding is provided (apart from hydrogen bonds) by covalent bonds between two sulfur atoms of two cysteine residues (so called disulfide bridges) at different places of a chain (tertiary protein structure) as well as between two cysteine residues in two separated protein subunits (quaternary protein structure). Both structures easily may be seen in insulin. As the bond energy of a covalent disulfide bridge is higher than the energy of a coordinate bond or hydrophobic interaction, higher disulfide bridges content leads to higher energy needed for protein denaturation. In general disulfide bonds are necessary in proteins functioning outside cellular space, and they do not change proteins' conformation (geometry), but serve as its stabilizers.[117] Within cytoplasm cysteine residues of proteins are saved in reduced state (i.e. in -SH form) by thioredoxins.[118]
This property manifests in following examples. Lysozyme is stable enough to be applied as a drug.[119] Feathers and hair have relative strength, and consisting in them keratin is considered indigestible by most organisms. However, there are fungi and bacteria containing keratinase, and are able to destruct keratin.
Many important cellular enzymes use prosthetic groups ending with -SH moieties to handle reactions involving acyl-containing biochemicals: two common examples from basic metabolism are coenzyme A and alpha-lipoic acid.[120] Cysteine-related metabolites homocysteine and taurine are other sulfur-containing amino acids that are similar in structure, but not coded by DNA, and are not part of the primary structure of proteins, take part in various locations of mammalian physiology.[121][122] Two of the 13 classical vitamins, biotin and thiamine, contain sulfur, and serve as cofactors to several enzymes.[123][124] In intracellular chemistry, sulfur operates as a carrier of reducing hydrogen and its electrons for cellular repair of oxidation. Reduced glutathione, a sulfur-containing tripeptide, is a reducing agent through its sulfhydryl (&#;SH) moiety derived from cysteine.
Methanogenesis, the route to most of the world's methane, is a multistep biochemical transformation of carbon dioxide. This conversion requires several organosulfur cofactors. These include coenzyme M, CH3SCH2CH2SO&#;3, the immediate precursor to methane.[125]
[
edit
]
Metalloproteins&#;in which the active site is a transition metal ion (or metal-sulfide cluster) often coordinated by sulfur atoms of cysteine residues[126]&#;are essential components of enzymes involved in electron transfer processes. Examples include plastocyanin (Cu2+) and nitrous oxide reductase (Cu&#;S). The function of these enzymes is dependent on the fact that the transition metal ion can undergo redox reactions. Other examples include many zinc proteins,[127] as well as iron&#;sulfur clusters. Most pervasive are the ferrodoxins, which serve as electron shuttles in cells. In bacteria, the important nitrogenase enzymes contain an Fe&#;Mo&#;S cluster and is a catalyst that performs the important function of nitrogen fixation, converting atmospheric nitrogen to ammonia that can be used by microorganisms and plants to make proteins, DNA, RNA, alkaloids, and the other organic nitrogen compounds necessary for life.[128]
Sulfur is also present in molybdenum cofactor.[129]
[
edit
]
[
edit
]
In humans methionine is an essential amino acid; cysteine is conditionally essential and may be synthesized from non-essential serine (sulfur donor would be methionine in this case). Dietary deficiency rarely happens in common conditions. Artificial methionine deficiency is attempted to apply in cancer treatment,[130] but the method is still potentially dangerous.[131]
Isolated sulfite oxidase deficiency is a rare, fatal genetic disease preventing production of sulfite oxidase, needed to metabolize sulfites to sulfates.[132]
[
edit
]
Effect of acid rain on a forest, Jizera Mountains, Czech RepublicThough elemental sulfur is only minimally absorbed through the skin and is of low toxicity to humans, inhalation of sulfur dust or contact with eyes or skin may cause irritation. Excessive ingestion of sulfur can cause a burning sensation or diarrhea,[135] and cases of life-threatening metabolic acidosis have been reported after patients deliberately consumed sulfur as a folk remedy.[136][137]
[
edit
]
When sulfur burns in air, it produces sulfur dioxide. In water, this gas produces sulfurous acid and sulfites; sulfites are antioxidants that inhibit growth of aerobic bacteria and a useful food additive in small amounts. At high concentrations these acids harm the lungs, eyes, or other tissues.[138] In organisms without lungs such as insects, sulfite in high concentration prevents respiration.[139]
Sulfur trioxide (made by catalysis from sulfur dioxide) and sulfuric acid are similarly highly acidic and corrosive in the presence of water. Concentrated sulfuric acid is a strong dehydrating agent that can strip available water molecules and water components from sugar and organic tissue.[140]
The burning of coal and/or petroleum by industry and power plants generates sulfur dioxide (SO2) that reacts with atmospheric water and oxygen to produce sulfurous acid (H2SO3).[141] These acids are components of acid rain, lowering the pH of soil and freshwater bodies, sometimes resulting in substantial damage to the environment and chemical weathering of statues and structures. Fuel standards increasingly require that fuel producers extract sulfur from fossil fuels to prevent acid rain formation. This extracted and refined sulfur represents a large portion of sulfur production. In coal-fired power plants, flue gases are sometimes purified. More modern power plants that use synthesis gas extract the sulfur before they burn the gas.
Hydrogen sulfide is about one-half as toxic as hydrogen cyanide, and intoxicates by the same mechanism (inhibition of the respiratory enzyme cytochrome oxidase),[142] though hydrogen sulfide is less likely to cause sudden poisonings from small inhaled amounts (near its permissible exposure limit (PEL) of 20 ppm) because of its disagreeable odor.[143] However, its presence in ambient air at concentration over 100&#;150 ppm quickly deadens the sense of smell,[144] and a victim may breathe increasing quantities without noticing until severe symptoms cause death. Dissolved sulfide and hydrosulfide salts are toxic by the same mechanism.
[
edit
]
[
edit
]
[
edit
]
[
edit
]
Sigel, Astrid; Freisinger, Eva; Sigel, Roland K.O., eds. (). Transition Metals and Sulfur: A Strong Relationship for Life. Guest Editors Martha E Sosa Torres and Peter M.H.Kroneck. Berlin/Boston: de Gruyter. pp. xlv+455. ISBN 978-3-11--7.
Sulfur at Wikipedia'sat Wikipedia's
sister projects
If you want to learn more, please visit our website calcium carbonate bulk.
Previous: None
Next: Calcium carbonate
If you are interested in sending in a Guest Blogger Submission,welcome to write for us!
All Comments ( 0 )