# What is the representation for Sulfur in organic matter?

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We often represent organic matter with the following equation:

$$(CH_2O)_x(NH_3)_y(H_3PO_4)_z ag{0}$$

For example, the organic matter with the Redfield ratio has the form of $$(CH_2O)_{106}(NH_3)_{16}(H_3PO_4)_1$$.

But if we want to put inside the element Sulfur ($$S$$), which form below should we use?

$$(CH_2O)_x(NH_3)_y(H_3PO_4)_z(H_2S)_m ag{1}$$

$$(CH_2O)_x(NH_3)_y(H_3PO_4)_z(S)_m ag{2}$$

$$(CH_2O)_x(NH_3)_y(H_3PO_4)_z(SO_4)_m ag{3}$$.

These different forms assume the different covalency of sulphur (-2, 0, or +6). Which form above should we take to describe the composition of organic matter with S?

I guess maybe Eq.(2) $$(CH_2O)_x(NH_3)_y(H_3PO_4)_z(S)_m$$? Because in this way, sulfur has the covalency of zero, which is the same as carbon (0).

I asked this question because I found many papers use the Eq.0 to build the mineralization of organic matter (e.g., O2 oxidation, [R1] in Table 2 here. See Fig.1 below). The amount of O2 depends on the assumption that carbon in OM has the covelency of zero (then, 1 mole of C corresponds to 1 mole of O2).

Since I didn't find a paper that put S into the OM compositon to balance the similar equation like [R1] in Fig.1, I am curious about which covalency value is "more common" for such an equation (because Sulfur's covalency can affect the amount of O2 needed).

## Abstract

Enrichment of organic matter with sulfur during early diagenesis has been amply documented in marine sediments. The importance of such reactions in lacustrine sediments is not as well appreciated. In this study the organic sulfur contents of sediments from seven lakes were compared, and the speciation of the sulfur in the humic acid fraction of the sedimentary organic matter was examined with X-ray photoelectron spectroscopy (XPS). Diagenetic enrichment of organic matter with sulfur occurred in five of seven lakes as evidenced by C:S ratios and stable isotope ratios. The availability of sulfide, organic matter, and reactive iron were not important determinants of the extent of organic S enrichment. The only environmental parameter that appeared to be related to S enrichment was lake trophic state. Together with data from the literature, our results suggest that sediments in most eutrophic lakes are enriched in organic S, while organic matter is enriched in only few oligotrophic lakes. Organic sulfides or thiols are the dominant forms of reduced organic S in the humic acids, and sulfur enrichment occurs primarily by formation of organic sulfides or thiols. Addition of S to polyunsaturated molecules could account for 5–10% of the S enrichment. Di- and polysulfides did not comprise a significant fraction of organic S in any of the sediment humic acids. Thiophenes could be identified tentatively only in the oldest (60 yr) sediment sample analyzed. Sulfoxides were observed in several samples. Lake trophic state and exposure to oxygen appear to be major factors influencing the extent and pathways of S addition to organic matter.

Present address: Dr. N. R. Urban, Dept. Civil and Environmental Engineering, Michigan Technological University, Dow Environ. Sci. & Engineering Bldg., 1400 Townsend Drive, Houghton, MI 49931-1295.

## Place of Microorganisms in Three Vital Cycles of Nature | Microbiology

The earth is composed of numerous elements, among which is a defined amount of carbon that must constantly be recycled to allow the formation of organic compounds of which all living things are made. Photosynthetic organisms take carbon in the form of carbon dioxide and convert it into carbohydrates using the sun’s energy and chlorophyll pigments.

The vast jungles of the world, the grassy plains of the temperate zones, and the plants of the oceans show the results of this process. Photosynthetic organisms, in turn, are consumed by grazing animals, fish, and humans who use some of the carbohydrates for energy and convert the remainder to cell parts. To be sure, some carbon dioxide is released back in respiration, but a major portion of the carbon is returned to the earth when the animal or plant dies.

It is here that the microorganisms exert their influence, for they are the primary decomposers of dead organic matter. Working in their countless billions in the water and soil, bacteria, fungi, and other microorganisms consume the organic substances and release carbon dioxide for reuse by the plants. This activity results from the concerted action of a huge variety of microorganisms, each with its own nutritional pattern of protein, carbohydrate, or lipid digestion.

Without the microorganisms, the earth would be a veritable garbage dump of animal waste, dead plants, and organic debris accumulating in implausible amounts.

But there is more. Microorganisms also break down the carbon-based chemicals produced by industrial processes including herbicides, pesticides, and plastics. In addition, they produce methane, or natural gas, from organic matter and are probably responsible for the conversion of plants to petroleum and coal deep within the recesses of the earth.

Moreover, many microorganisms trap CO2 from the atmosphere and form carbohydrates to supplement the results of photosynthesis. In these activities, the microorganisms represent a fundamental underpinning of organic creation.

#### 2. Sulfur Cycle:

The sulfur cycle may be defined in more specific terms than the carbon cycle. Sulfur is a key constituent of such amino acids as cystine, cysteine, and methionine, all of which are important components of proteins. Proteins are deposited in water and soil as living things die, and bacteria decompose the proteins and break down the sulfur-containing amino acids to yield various compounds including hydrogen sulfide.

Sulfur may also be released in the form of sulfate molecules commonly found in organic matter. Anaerobic bacteria such as those of the genus Desulfovibrio subsequently convert sulfate molecules to hydrogen sulfide.

The next set of conversions involves several genera of bacteria, including members of the genera Thiobacillus, Beggiatoa, and Thiothrix. These bacteria release sulfur from hydrogen sulfide during their metabolism and convert it into sulfate. The sulfate is now available to plants where it is incorporated into the sulfur-containing amino acids. Consumption by animals and humans completes the cycle.

#### 3. Nitrogen Cycle:

The cyclic transformation of nitrogen is of paramount importance to life on Earth. Nitrogen is an essential element in nucleic acids and amino acids. Although it is the most common gas in the atmosphere (about 80 percent of air), animals cannot use nitrogen in its gaseous form, nor can any but a few species of plants. The animals and plants thus require the assistance of microorganisms to trap the nitrogen.

The nitrogen cycle begins with the deposit of dead plants and animals in the soil. In addition, nitrogen reaches the soil in urea contained in urine. A process of digestion and putrefaction by soil bacteria and other microorganisms follows, thus yielding a mixture of amino acids. Amino acids are further broken down in microbial metabolism, and the ammonia that accumulates may be used directly by plants.

Next, mineralization takes place. In this process, complex organic compounds are finally converted to inorganic compounds and additional ammonia. Much of the ammonia is converted to nitrite ions by Nitrosomonas species, a group of aerobic Gram-negative rods. In the process, the bacteria obtain energy for their metabolic needs.

The nitrite ions are then converted to nitrate ions by species of Nitrobacter, another group of aerobic Gram-negative rods, which obtain energy from the process. Nitrate is a crossroads compound: it can be used by plants for their nutritional needs, or it can be liberated as atmospheric nitrogen by certain microorganisms.

For the nitrogen released to the atmosphere, a reverse trip back to living things is an absolute necessity for life to continue as we know it. The process is called nitrogen fixation. Once again microorganisms in water and soil play a key role because they possess the enzyme systems that trap atmospheric nitrogen and convert it to compounds useful to plants. In nitrogen fixation, gaseous nitrogen is incorporated to ammonia that fertilizes plants.

Two general types of microorganisms are involved in nitrogen fixation: free-living species and symbiotic species. Free-living species include bacteria of the genera Bacillus, Clostridium, Pseudomonas, Spirillum, and Azotobacter, as well as types of cyanobacteria and certain yeasts. Generally, the free-living species fix nitrogen during their growth cycles. The nitrogen-fixing ability of these species cannot be overemphasized.

Symbiotic species of nitrogen-fixing microorganisms live in association with plants that bear their seeds in pods. These plants, known as legumes, include peas, beans, soybeans, alfalfa, peanuts, and clover. Species of Gram-negative rods known as Rhizobium infect the roots of the plants and live within swellings, or nodules, in the roots.

Although complex factors are involved, the central theme of the relationship is that Rhizobium fixes nitrogen and makes nitrogen compounds available to the plant while taking energy-rich carbon compounds in return. The bulk of the nitrogen compounds accumulates when Rhizobium cells die.

Legumes then use the compounds to construct amino acids and, ultimately, protein. Animals consume the soybeans, alfalfa, and other legumes and convert plant protein to animal protein, thereby completing the cycle.

Humans have long recognized that soil fertility can be maintained by rotating crops and including a legume. The explanation lies in the ability of rhizobia to fix nitrogen within the nodules of legumes. So much nitrogen is captured, in fact, that the net amount of nitrogen in the soil actually increases after a crop of legumes has been grown. When cultivating legumes, there is no need to add nitrogen fertilizer to the soil.

In addition, when crops such as clover or alfalfa are plowed under, they markedly enrich the soil’s nitrogen content. Thus, humans are indebted to microorganisms for such edible plants as peas and beans, as well as for the indirect products of nitrogen fixation, namely, steaks, hamburgers, and milk.

Dittmar et al. proposed that mixing alone can explain our observed decrease in marine dissolved organic sulfur with age. However, their simple model lacks an explanation for the origin of sulfur-depleted organic matter in the deep ocean and cannot adequately reproduce our observed stoichiometric changes. Using radiocarbon age also implicitly models the preferential cycling of sulfur that they are disputing.

Dittmar and co-workers (1) claimed that the distribution of marine dissolved organic sulfur (DOS) reported in Ksionzek et al. (2) could be explained by simple water mass mixing alone. The authors calculated separate mixing models for the solid-phase extractable (SPE) fraction of dissolved organic carbon (DOC), nitrogen (DON), and DOS. They based their calculation on radiocarbon age and two end-members—deep and surface ocean water—that differed in concentration, elemental composition, and radiocarbon age of the dissolved organic matter (DOM).

We appreciate the interest in our publication however, we disagree with their conclusions for three fundamental reasons: (i) Their mixing hypothesis considers deep-sea DOM as an independent end-member without reasoning for its origin or formation processes. (ii) Mixing without removal cannot adequately explain the stoichiometric changes that we observed. (iii) The authors mistakenly assumed that we exclusively addressed the removal of refractory DOS. Each of these aspects is addressed in detail below and rules out that mixing alone can explain the distribution of DOS and the depletion of nonlabile DOS.

We are well aware of the fact that the ocean consists of different water masses influenced by seasonal changes of the mixed-layer, deep-mixing, and circulation. Dittmar et al. outlined the accepted view that production in the ocean surface is the source for deep-sea DOM. Many previous stoichiometric studies [e.g., (3)] showed depletion of DON and dissolved organic phosphorus relative to DOC from surface to deep water, consistent with the DOS depletion and respective stoichiometric changes that we observed. Nonetheless, in their mixing model, Dittmar et al. treated surface and deep DOM as independent end-members (conservative mixing). Because the ultimate source of deep-ocean DOM is primary production, removal processes are fundamental to explain differences in concentration and stoichiometry (i.e., DOSSPE/DOCSPE ratio), as well as the differing methionine-S yield between surface and deep DOM that we observed. Calculating the DOSSPE removal exclusively for the meso- and epipelagic showed little effect on the rate coefficient (Fig. 1).

Circle sizes represent the global sulfur inventory in phytoplankton and the minimum inventory of marine DOS. Squares represent annual fluxes. Removal of nonlabile DOS (within the dotted circle) represents less than one per mil of the annual sulfur assimilation by primary production (1360 Tg S year −1 ). Calculating the removal rate for DOS above the pycnocline (<1000 m), where existence of active removal is indisputable, only marginally reduces the coefficient compared with the calculation for the entire water column calculated in (2) (gray box). The major future scientific challenge is the unaddressed mineralization of organic sulfur derived from primary production and its conversion into nonlabile DOS (black dotted arrows).

Our results are in agreement with many previous studies reporting microbial alteration of marine DOM composition (38). Dittmar and co-workers cited a recent study (9) that showed localized removal of refractory DOC in the deep Pacific. Hansell and Carlson conclude that the removal mechanisms are unknown and hypothesize that (i) the release of exoenzymes by microbial assemblages could lead to uptake of recalcitrant compounds, (ii) solubilization of sinking particles could support cometabolism, or (iii) sinking particles or gel formation could remove refractory DOC. Each of these processes would also contribute to our calculated DOS net removal.

By using radiocarbon age as a measure for mixing, Dittmar et al. introduced an inherent inconsistency: On the one hand, they correctly emphasized that bulk radiocarbon age is affected by preferential removal of labile DOM constituents above the pycnocline on the other hand, they used radiocarbon age to infer conservative mixing over the entire water column.

Although it is unclear how Dittmar et al. “fine-tuned” [caption, figure 2 of (1)] end-member values to match their exponents to our approach, they reproduced our gradients by their mixing models. However, the authors neglected to compare relative differences between their mixing models [see figure 2 of (1)] and the resulting changes in elemental stoichiometry if it were truly conservative mixing alone, each element would be equally affected. A simple way to illustrate this is to compare relative differences between their end-member concentrations for deep and surface water. The concentrations of DOSSPE (0.08 μmol L −1 ) and DONSPE (0.7 μmol L −1 ) in the deep are 50% lower than surface concentrations (0.16 and 1.4 μmol L −1 , respectively), whereas DOCSPE is only reduced by 39%.

Mass spectrometry data from this and previous studies (4, 5) provide independent measures that mixing alone might model but cannot explain complex compositional DOM dynamics. In a mixing-only scenario with two end-members, one would expect a correlation of the peak magnitude for each observed mass with the mixing ratio (and age). Instead, we observed that only 65% of the total peak magnitude in the mass spectra correlated with radiocarbon age, whereas 35% was not correlated.

Although the SPE applied does not recover some of the most polar labile compounds, it does include molecules that are cycling on different time scales in the ocean, which led us to define the term “nonlabile” DOSSPE (2). In the productive surface layer, this is reflected in higher methionine content, younger DOMSPE radiocarbon age and unique sulfur-containing formulas. Thus our DOSSPE removal rate encompasses degradable compounds and processes that are faster than those relevant for refractory DOM alone. It should be noted that in figure 3 of (1), the removal was assigned incorrectly as “refractory” and the sulfate reservoir should be 1.2 × 10 9 Tg S. Most important, the rate demonstrates that 99.9% of the sulfur assimilated is subject to rapid cycling, whereas the nonlabile DOSSPE removal discussed by Dittmar et al. only represents a very minor flux (Fig. 1).

Dittmar et al. also claimed that persistent sulfonates dominate the DOS pool and mix conservatively in the ocean, based on a previous study using a nonquantitative method in which steric hindrance was excluded a priori (10). Previous studies indeed identified relatively unreactive alkylsulfonates in marine DOM (11), which are potentially derived from anthropogenic surfactants (12). However, other studies, using independent methods, quantified additional reduced sulfur groups such as thioethers (identified as methionine in our data set) and thiols (13), consistent with the fact that the amino acids methionine and cysteine are primary biogenic precursors of DOS.

Dittmar et al. overlooked that we explicitly mentioned that the carbon in sulfur-containing compounds most likely cycles on different time scales than bulk DOC. We are well aware that changes in radiocarbon age are likely to be faster than the time elapsed, owing to the removal of the labile and young DOM fraction (5). Such a partitioning effect would have an effect on the absolute number for the net DOS removal (Fig. 1) but cannot support their mixing theory. On the contrary, the insight that DOS cycles faster than DOC supports the presence of a removal process.

## 2. Methods and Materials

### 2.1. Site Descriptions

[7] Organic soil horizon samples were collected from three well-characterized northern forests, Marsh-Billings-Rockefeller National Historical Park (MBRNHP) in the piedmont of Vermont, Hubbard Brook Experimental Forest (HBEF) in the White Mountains of New Hampshire, and Whiteface Mountain in the Adirondack Mountains of New York. Located near Woodstock, Vermont, MBRNHP contains plantation-style stands of red pine (Pinus resinosa), white pine (Pinus strobes), and Norway spruce (Picea abies), with adjacent stands of northern hardwood forest (primarily sugar maple (Acer saccharum), beech (Fagus grandifolia), yellow birch (Betula alleghaniensis)) that are 50 to 100 years (a) old where soils are well characterized [ Lautzenheizer, 2002 Schroth et al., 2007 ]. The Whiteface Mountain site consists of > 100-a-old forests of balsam fir (Abies balsamea) and red spruce (Picea rubens) typical of high-elevation forests in the northeastern United States, where extensive monitoring of ecosystem and soil chemistry has been performed [ Miller et al., 1993 ]. Samples from HBEF, an extremely well characterized long-term ecological research site [ Likens et al., 2002 ], were collected from both low-elevation northern hardwood forests (same general composition as those at MBRNHP) and high-elevation red spruce and balsam fir forests that were also at least 100 a old. Samples were collected and archived by researchers at HBEF in watershed 5 in 1983 prior to tree harvesting efforts within this watershed and sampling methods are fully described by Zhang et al. [1999] .

### 2.2. Litter Decomposition Study and Sectioned Organic Soil Horizons

[8] Litter samples were collected from the surface of the forest floor (Oi) from each forest type at MBRNHP. The samples collected from MBRNHP consisted of litter from red pine white pine, northern hardwood, old Norway spruce (∼100 a) and young Norway spruce (∼50 a) stands. Litter samples were then allowed to decompose under moist conditions in a closed system that prevented leaching losses of dissolved and colloidal organic matter, with weekly wetting (to the appearance of homogenous ∼50% moisture content by mass similar to that observed in Oi horizons after a precipitation event) to enhance decomposition. Immediately upon sampling organic matter from the experiment, samples were refrigerated (∼4°C) to limit further decomposition. Two decomposition experiments were conducted at different times for 6 month periods. The first began in winter of 2003 and the second began in summer of 2004. Samples were collected from the same general sites at MBRNHP, but on different sampling trips, so they provide us with some perspective on variability in the system and experimental replication. The only difference in experimental design was that the second experimental litter samples were finely ground. Carbon mineralization was measured by mass loss and changes in C and N concentrations measured with a Carlo Erba C-H-N analyzer. In addition, A horizon soil samples were collected from soil pits within each forest type at MBRNHP based on visual characterization. These latter samples were assumed to represent highly decomposed and hence humified organic matter from the same initial litter source used for decomposition experiments, which allowed us to examine S speciation along a decomposition continuum beyond that available from the laboratory incubations (at least 100 a).

[9] Subhorizons (i.e., Oi, Oe, Oa) from the forest floor were collected at Whiteface Mountain and HBEF in discrete intervals corresponding with their extent of humification by visual characterization. At Whiteface Mountain, ∼10 cm sections of the spruce/fir forest floors were sectioned in centimeter-scale resolution and divided into Oi, Oe and Oa subsamples. At HBEF, forest floor samples were collected under high-elevation conifer forests primarily consisting of red spruce and balsam fir and lower elevation northern hardwood forests primarily consisting of sugar maple, American beech, and yellow birch. These forest floors were sectioned into two subsamples (Oi/e and Oa), ground and archived in 1983 as part of a previous study (see Zhang et al. [1999] for a complete description of sampling protocol). The goal of collecting sectioned forest floor samples was to obtain S species data in soils that would represent a decomposition continuum under field conditions that allow for leaching of labile S, and bridge some of the time gap between experimental (6 month) and A horizon (>100 a) data from MBRNHP. These samples also provide replication for processes observed in experimental and A horizon data from similar pedochemical systems to MBRNHP, but at different sites with slightly different environmental conditions specific to their site locations.

### 2.3. Sulfur Speciation

[10] All samples were analyzed by K-edge XANES spectroscopy to determine S speciation by fraction of total S. XANES spectra were collected at beam line X19A at the National Synchrotron Light Source (NSLS), Brookhaven National Laboratory, Brookhaven, New York. Soil samples were ground and homogenized with a mortar and pestle and spread into a thin (∼1 mm) layer on 25.4 × 38.1 mm sample holders with Whatman (No. 1) filter paper. On most samples, a thin (3-μm) Mylar film was added to prevent evaporation during analysis and preserve the sample oxidation state. The S analysis on X19A was performed under ambient (moist, He purged) conditions [ Hutchison et al., 2001 Waldo et al., 1991 Xia et al., 1998 ]. Spectra were collected in fluorescence mode using a one-element passive implanted plana silicon (PIPS) detector. Spectra were calibrated using a 28mmol sulfate standard solution (2483 eV). The background was subtracted, and the step-edge height normalized to unity for all samples prior to data processing.

[11] Sulfur speciation was identified and quantified using WinXAS [ Ressler, 1998 ] for least squares fitting of spectra to known standards following Bostick et al. [2005] . Spectral components of each sample were identified by comparison to those of organic S standards and the fractional abundance of each component was then determined by linear combinations to yield theoretical spectra (Figure 1) [ Bostick et al., 2005 Waldo et al., 1991 ]. The quality of fit can be examined statistically by calculating the residual and χ 2 of each sample fit. Five standards were assumed to best represent organic S species found in these soils: cystine and methionine (representative of carbon-bonded sulfur sulfides), dimethlysulfoxide (model intermediate oxidation state sulfoxide, R-SO-R), cysteic acid (a model sulfonate, R-SO3-H) and dodecyl sulfate (a model ester sulfate) (Table 1). It should be clearly noted here that the use of these standards does not imply that the entire fraction of S fit to each of the standards must exist as these exact compounds, but that the bonding and valence of S in the identified fraction is similar to the representative standard that was used to fit that portion of the spectra.

Standard Peak Position, eV
Cystine 2473.2
Methionine 2473.8
Dimethylsulfoxide 2475.6
Sulfonate 2481.5
Organic Sulfate 2482.5

[12] Linear combination (LC) fitting was used to determine relative proportions of each S species present in the sample. Linear combinations of reference spectra, each of which is representative of a class of S species were fit to normalized spectra over the range of 2465 to 2488 eV (Figure 1). Fit parameters with reasonable χ 2 values typically ranged from 0.3 to 4.0. Residuals ranged from 2.7 to 10.5. The sum of linear coefficients determined by fitting the data is ideally equal to 1 and is a useful indicator of fit quality. Sums of all linear coefficients were close to 1 with a range of 0.9 to 1.15 however, the reported speciation is normalized to unity. The precision of these analyses was estimated by analyzing known mixtures of S reference materials. Precision is best for ester sulfate because of its intense white line feature—typically a 1–2% change in sulfate fraction was routinely measured. Although XANES is less sensitive to sulfides (which lack a strong white line), the method precision was about 3% for sulfides for normalized spectra. Fitting accuracy is similar, usually within a few percent for a spectrum, and impacted most strongly by background subtraction and normalization. Overall, statistical analysis suggests an error of 2–3% for comparative purposes of speciation data presented here between samples, and an accuracy of 5% of S species composition in the litter.

## A sulfur molecule to block the coronavirus

The cell membrane is impermeable to viruses: to get inside and infect a cell, they use a range of strategies to exploit the cellular and biochemical properties of the membranes. The thiol-mediated uptake of organic molecules similar to alcohols, where oxygen is replaced by a sulfur atom, is one of the entry mechanisms, with its use by Human Immunodeficiency Virus (HIV) demonstrated a few years ago. No effective inhibitor is currently available because of the robustness of the chemical reactions and bonds at work.

A research group from the University of Geneva (UNIGE) has identified inhibitors that are up to 5,000 times more effective than the one most often used today. Preliminary tests -- published and available free of charge in Chemical Science, the flagship journal of the Royal Society of Chemistry -- demonstrate the blocking of the cellular entry of viruses expressing the SARS-CoV-2 proteins. The study paves the way for research into new antivirals.

Since 2011, the laboratory led by Professor Stefan Matile in UNIGE's Department of Organic Chemistry, member of the two National Centre of Competence in Research (NCCR) " Chemical Biology " and " Molecular Systems Engineering ," has been investigating the way thiols react with other structures containing sulfur: sulfides, molecules where sulfur is combined with another chemical element. "These are very special chemical reactions because they can change state dynamically," begins Professor Matile. In fact, covalent bonds, based on sharing electrons between two atoms, freely oscillate between sulfur atoms, depending on conditions.

Passing the cell membrane

Sulfur compounds are present in nature, particularly on the membrane of eukaryotic cells and on the envelope of viruses, bacteria and toxins. Studies suggest that they play a role in one of the mechanisms -- known as thiol-mediated uptake -- that enables the very difficult passage from outside to inside the cell. This key step involves the dynamic bond between thiols and sulfides. "Everything that approaches the cell can connect to these dynamic sulfur bonds," continues Professor Matile. "They cause the substrate to enter the cell either by fusion or endocytosis, or by direct translocation through the plasma membrane into the cytosol." Studies a few years ago showed that the entry of HIV and diphtheria toxin use a mechanism involving thiols.

"This chemistry is well known, but no one believes it was involved in cellular uptake," says the professor, who explains that this scepticism on the part of the scientific community is probably due to the lack of inhibitor available to test it. "The involvement of membrane thiols in cellular uptake is usually tested by inhibition using Ellman's reagent. Unfortunately, this test isn't always reliable, partly because of the relatively low reactivity of Ellman's reagent faced with the high reactivity of thiols and sulfides."

The quest for an inhibitor

While Stefan Matile's laboratory was working on writing a bibliographic review on the subject during the first Swiss lockdown in the spring of 2020, it began looking for a potential inhibitor, thinking that it could prove useful as an antiviral against SARS-CoV-2. Professor Matile's coworkers reviewed potential inhibitors and carried out in vitro cellular uptake tests of sulfur molecules marked with fluorescent probes to assess their presence inside cells using fluorescence microscopy.

Molecules up to 5,000 times more effective than Ellman's reagent were identified. With these excellent inhibitors in hand, the laboratory threw itself into viral tests with the help of Neurix, a Geneva-based start-up. They modified laboratory viruses, called lentivectors, expressing the proteins of the SARS-CoV-2 viral envelope pandemic safely and harmlessly. One of the inhibitors was found to be effective at blocking the virus's entry into cells in vitro. "These results are at a very early stage and it would be entirely speculative to say we've discovered an antiviral drug against coronavirus. At the same time, this research shows that thiol-mediated uptake could be an interesting line of enquiry for developing future antivirals," concludes Professor Matile.

## Biologically Significant Functional Groups

In addition to containing carbon atoms, biomolecules also contain functional groups&mdashgroups of atoms within molecules that are categorized by their specific chemical composition and the chemical reactions they perform, regardless of the molecule in which the group is found. Some of the most common functional groups are listed in Figure (PageIndex<8>). In the formulas, the symbol R stands for &ldquoresidue&rdquo and represents the remainder of the molecule. R might symbolize just a single hydrogen atom or it may represent a group of many atoms. Notice that some functional groups are relatively simple, consisting of just one or two atoms, while some comprise two of these simpler functional groups. For example, a carbonyl group is a functional group composed of a carbon atom double bonded to an oxygen atom: C=O. It is present in several classes of organic compounds as part of larger functional groups such as ketones, aldehydes, carboxylic acids, and amides. In ketones, the carbonyl is present as an internal group, whereas in aldehydes it is a terminal group.

Figure (PageIndex<8>): Common functional groups.

Hydrogen bonds between functional groups (within the same molecule or between different molecules) are important to the function of many macromolecules and help them to fold properly into and maintain the appropriate shape for functioning. Hydrogen bonds are also involved in various recognition processes, such as DNA complementary base pairing and the binding of an enzyme to its substrate, as illustrated in Figure (PageIndex<9>).

Figure (PageIndex<9>): Hydrogen bonds connect two strands of DNA together to create the double-helix structure.

## Abstract

Sulfur has a unique role in the various transformations of organic matter, from early diagenesis to the late stages of catagenesis. This activity of sulfur is facilitated by its ability to exist in many oxidation states, and to form catenated (polysulfidic) and mixed oxidation state species. This paper deals with mechanistic aspects of the transformations of sedimentary organic sulfur in particular, it focuses on the transformations of polysulfidic sulfur. The nucleophilic introduction of these forms into organic matter generates thermally labile polysulfide cross-linked polymers during early diagenesis. The thermal processes occurring during later diagenesis, and catagenesis stabilize the sulfur in polymeric structures by forming new functionalities of sulfur (for example, thiophenic), and eliminating H2S/S8. At higher temperatures, the latter can reincorporate into organic matter or can aid in the oxidation of organic matter. While the introduction of sulfur into sedimentary organic matter occurs mainly during the early diagenesis, and is ionically controlled, the later catagenetic transformations probably are controlled by radical mechanisms.

## Addressing multiple sclerosis using organic sulfur

Customer writes, “My wife and I been taking organic sulfur for a month. I’ve been suffering from multiple sclerosis for years and was hoping to see an immediate increase in energy and an improvement in my overall health.

While my wife has noticed that her joints are much more flexible and her hair feels stronger and not as dry, I haven’t seen any material changes, other than gaining a few pounds and feeling hungrier than I did before. Besides organic sulfur, I also take Vitamin C and potassium dissolved in water. Would either of these interfere with sulfur?”

My Response

Taking organic sulfur seems to increase one’s metabolism rate. I know that when I first started taking the supplement that I felt the need to eat more frequently.

The standard protocol is to take your sulfur-and-water mixture first, then wait a half hour before taking any medications or dietary supplements. It’s possible that either of those two dietary products – even if they are originally packaged in liquid or crystalline form – may contain a compound that interferes with the full intake of sulfur. To err on the conservative side, make sure you don’t take your vitamin and sulfur mixtures at the same time or right after each other.

In regards to the amount of time needed to notice improvements in your health, it should be noted that it takes 7 years to regenerate all the soft tissue cells. When enough water supplies oxygen for sulfur to transport, then the myelinated nerves will begin to regenerate. While four weeks is a good start, nerve cells do not regenerate overnight. Pay close attention to improvements to your skin, hair, and nails.

Myelinated nerve: A nerve cell in which the axon is surrounded by a layer of Schwann cell membranes of myelin sheath. This type of nerve cell is found in the peripheral nervous system (especially the sensory and motor neurons) and the white matter of central nervous system.

## One-pot synthesis towards sulfur-based organic semiconductors

Yellow and gray colors on the molecule represent sulfur and carbon atoms respectively. Thiophene-fused PAHs have found uses as transistors. Credit: ITbM, Nagoya University

Thiophene-fused polycyclic aromatic hydrocarbons (PAHs) are known to be useful as organic semiconductors due to their high charge transport properties. Scientists at Nagoya University have developed a short route to form various thiophene-fused PAHs by simply heating mono-functionalized PAHs with sulfur. This new method is expected to contribute towards the efficient development of novel thiophene-based electronic materials.

Nagoya, Japan - Dr. Lingkui Meng, Dr. Yasutomo Segawa, Professor Kenichiro Itami of the JST-ERATO Itami Molecular Nanocarbon Project, Institute of Transformative Bio-Molecules (ITbM) of Nagoya University and Integrated Research Consortium on Chemical Sciences, and their colleagues have reported in the Journal of the American Chemical Society, on the development of a simple and effective method for the synthesis of thiophene-fused PAHs.

Thiophene-fused PAHs are organic molecules composed of multiple aromatic rings including thiophene. Thiophene is a five-membered aromatic ring containing four carbon atoms and a sulfur atom. Thiophene-fused PAHs are known to be one of the most common organic semiconductors and are used in various electronic materials, such as in transistors, organic thin-film solar cells, organic electro-luminescent diodes and electronic devices. More recently, they have found use in wearable devices due to their lightweight and flexibility.

Thienannulation (thiophene-annulation) reactions, a transformation that makes new thiophene rings via cyclization, leads to various thiophene-fused PAHs. Most conventional thienannulation methods require the introduction of two functional groups adjacent to each other to form two reactive sites on PAHs before the cyclization can take place. Thus, multiple steps are required for the preparation of the substrates. As a consequence, a more simple method to access thiophene-fused PAHs is desirable.

Conventional methods require 2 functional groups on PAHs, whereas the method requires only 1 functional group. Credit: ITbM, Nagoya University

A team led by Yasutomo Segawa, a group leader of the JST-ERATO project, and Kenichiro Itami, the director of the JST-ERATO project and the center director of ITbM, has succeeded in developing a simple and effective method for the formation of various thiophene-fused PAHs. They have managed to start from PAHs that have only one functional group, which saves the effort of installing another functional group, and have performed the thienannulation reactions using elemental sulfur, a readily available low cost reagent. The reactions can be carried out on a multigram scale and can be conducted in a one-pot two-step reaction sequence starting from an unfunctionalized PAH. This new approach can also generate multiple thiophene moieties in a single reaction. Hence, this method has the advantage of offering a significant reduction in the number of required steps and in the reagent costs for thiophene-fused PAH synthesis compared to conventional methods.

The researchers have shown that upon heating and stirring the dimethylformamide solution of arylethynyl group-substituted PAHs and elemental sulfur in air, they were able to obtain the corresponding thiophene-fused PAHs. The arylethynyl group consists of an alkyne (a moiety with a carbon-carbon triple bond) bonded to an aromatic ring. The reaction proceeds via a carbon-hydrogen (C-H) bond cleavage at the position next to the arylethynyl group (called the ortho-position) on PAHs, in the presence of sulfur. As the ortho-C-H bond on the PAH can be cleaved under the reaction conditions, prior functionalization (installation of a functional group) becomes unnecessary.

Arylethynyl-substituted PAHs are readily accessible by the Sonogashira coupling, which is a cross-coupling reaction to form carbon-carbon bonds between an alkyne and a halogen-substituted aromatic compound. The synthesis of thiophene-fused PAHs can also be carried out in one-pot, in which PAHs are subjected to a Sonogashira coupling to form arylethynyl-substituted PAHs, followed by direct treatment of the alkyne with elemental sulfur to induce thienannulation.

Structures of thiophene and thiophene-fused PAHs. Credit: Institute of Transformative Bio-Molecules (ITbM), Nagoya University

"Actually, we coincidentally discovered this reaction when we were testing different chemical reactions to synthesize a new molecule for the Itami ERATO project," says Yasutomo Segawa, one of the leaders of this study. "At first, most members including myself felt that the reaction may have already been reported because it is indeed a very simple reaction. Therefore, the most difficult part of this research was to clarify the novelty of this reaction. We put in a significant amount of effort to investigate previous reports, including textbooks from more than 50 years ago as well as various Internet sources, to make sure that our reaction conditions had not been disclosed before," he continues.

The team succeeded in synthesizing more than 20 thiophene-fused PAHs. They also revealed that multiple formations of thiophene rings of PAHs substituted with multiple arylethynyl groups could be carried out all at once. Multiple thiophene-fused PAHs were generated from three-fold and five-fold thienannulations, which generated triple thia[5]helicene (containing three thiophenes) and pentathienocorannulene (containing five thiophenes), respectively. The pentathienocorannulene was an unprecedented molecule that was synthesized for the first time.

"I was extremely happy when I was able to obtain the propeller-shaped triple thia[5]helicene and hat-shaped pentathienocorannulene, because I have always been aiming to synthesize exciting new molecules since I joined Professor Itami's group," says Lingkui Meng, a postdoctoral researcher who mainly conducted the experiments. "We had some problems in purifying the compounds but we were delighted when we obtained the crystal structures of the thiophene compounds, which proved that the desired reactions had taken place."

Thiophene moieties formed in the reaction are colored red. Credit: ITbM, Nagoya University

"The best part of this research for me is to discover that our C-H functionalization strategy on PAHs could be applied to synthesize structurally beautiful molecules with high functionalities," says Segawa. "The successful synthesis of a known high-performance organic semiconductive molecule, (2,6-bis(4-n-octylphenyl)- dithieno[3,2-b:2?,3?-d]thiophene (the lower right of Figure 4), from a relatively cheap substrate opens doors to access useful thiophene compounds in a rapid and cost-effective manner."

"We hope that ongoing advances in our method may lead to the development of new organic electronic devices, including semiconductor and luminescent materials," say Segawa and Itami. "We are considering the possibilities to make this reaction applicable for making useful thiophene-fused PAHs, which would lead to the rapid discovery and optimization of key molecules that would advance the field of materials science."