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Chapter 4 Application of Designing Safer Chemicals. 4.1 Isosteric Replacement of Carbon with Silicon ( 用硅对碳进 行等电排置换 ) in the Design of Safer Chemicals 4.2 Designing Biodegradable Chemicals 4.3 Designing Aquatically Safer Chemicals
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4.1Isosteric Replacement of Carbon with Silicon (用硅对碳进 行等电排置换) in the Design of Safer Chemicals • 4.2 Designing Biodegradable Chemicals • 4.3 Designing Aquatically Safer Chemicals • References
4.1 Isosteric Replacement of Carbon with Silicon in the Design of Safer Chemicals (用硅对碳进行等电排置换)
Differences between Silicon compounds and Carbon compounds Silicon is an Isostere of Carbon Examples of isosteric replacement of carbon with silicon for the design of safer chemicals The degradation and oxidative metabolism of organic silicon compounds
4.1.1 Silicon is an Isosteric atom of Carbon Common Features of Silicon and Carbon • grouped in column 4A of the Periodic Table • having many chemical similarities： tetravalent, tetrahedral, and form stable bonds with carbon. 金刚石 碳化硅 四川大学化学学院
Silicon is an Isosteric atom of Carbon Organic derivatives of silicon generally have no intrinsic toxicity, in contrast with the other Group 4A elements germanium (Ge), tin (Sn), and lead (Pd). From a toxicity perspective, silicon is the only Group 4A element that is a suitable replacement for carbon. In addition, silicon is an abundant, inexpensive element and one that is available in a variety of forms.
Urethanes (尿烷), natural analogs of the neuro-transmitter (神经传递质) acetylcholine (乙酰胆碱)(1), were found to be antagonists (拮抗药)of (1) with identical dose-response curves .Interestingly, silane (silicon) was much less toxic to mice than urethane (carbon), and exhibited muscle relaxant properties . Examples: 四川大学化学学院
Acetylcholine (乙酰胆碱) Urethane (尿烷) Muscarinic Antagonistis（蝇覃碱拮抗剂） • The tert-butyl (叔丁基) and trimethylsilyl (三甲基硅) groups function simply as isosteres of trimethylammonium (三甲基铵).
Carbamate (氨基甲酸酯) insecticide and its silicon analog were found to have similar toxicity to the house fly. Carbamate Silicon substituted Isostere of carbamate (More degradable, less toxic to human and environment)
4.1.2 Differences between Silicon and Carbon Compounds Silicon is the element most similar to carbon, however it is not a generic replacement for all carbon atoms and certain strict limitations apply. Double bonds to silicon, and three-membered rings containing silicon, are unstable to air and moisture. Single bonds from silicon to heteroatoms such as nitrogen and oxygen are strong but can hydrolyze readily.
A subtle yet influential difference in atomic size exists for silicon and carbon , important differences in chemical reactivity also exist. When silicon is proximal (最接近的) to unsaturation, as in a vinyl (乙烯基) or allyl (丙稀基) silane, the compounds are stable, but unlike their carbon analogs, they are subject to acid catalyzed silicon-carbon bond cleavage. Breaking of C－Si bond is easy. Herein lies a potential avenue (方法) for the design of environmentally degradable products.
4.1.3 The degradation and oxidative metabolism of organic silicon compound An important component of designing safer chemicals is predicting their environment fate, and both abiotic (非生物) degradation and biological oxidation can play a role. Designing chemicals that will biodegrade to innocuous products is highly desirable, and isosteric substitution of carbon with silicon in many cases may enhance abiotic degradation and biological oxidation .
Abiotic Degradation • Currently the major environmental source of organosilane is silicone polymer (聚硅酮)(siloxanes硅氧烷), primarily polymers of 1,1-dimethyl silanediol. • Siloxanes were once thought to be environmentally stable, but are now known to be depolymerized in the presence of water and soil. 四川大学化学学院
Silicone polymer (Siloxanes, 聚硅酮) depolymerize in the presence of water and soil to silicates finally
4.1.4 Examples for the Design of Safer Chemicals Using Silicon Substitution for Carbon Example 1： Silane Analogs of DDT Example 2：Organosilane Fungicides (杀真菌剂)
DDT Silane Analogs of DDT • In an early effort to design a more benign version of DDT, a number of silane analogs such as the DDD analog were prepared with the anticipation that these would be less environmentally persistent. 四川大学化学学院
Silane Analogs of DDT • The presence of the readily oxidized silicon-hydrogen bond would have been one source of instability, both in the environment and in vivo. • More significant for this research, however, was an SAR study that found the overall size of the DDT molecule strongly correlated with bioactivity, implicating the atomic size of the central silicon for the lack of insect toxicity for DDD and congeners(同类). 四川大学化学学院
Organosilane Fungicides • As a novel entry into the class of triazole (三唑) fungicides (杀真菌剂), Meberg and coworkers prepared a series of silane analogs. • One of these, flusilazole (氟苯代硅三唑) proved to be a highly effective cropfungicide（谷类防真菌） and is now a major commercial product . 四川大学化学学院
Metabolism Flusilazole （氟苯代硅三唑） Usage: cropfungicide
4.1 Isosteric Replacement of Carbon with Silicon (用硅对碳进行等电排置换)in the Design of Safer Chemicals • 4.2 Designing Biodegradable Chemicals • 4.3 Designing Aquatically Safer Chemicals • References 四川大学化学学院
The safer chemical eliminatesthe production and release of more persistent and potentially hazardous substitutes through molecular designto enhance biodegradabilityto non-toxic products. Enhanced biodegradability is also a worthy goal precisely because pollution cannot always be prevented at the source. 四川大学化学学院
The Microbial Basis of Biodegradation Chemical Structure and Biodegradability Group Contribution Method for Predicting Biodegradability Examples of Designing Biodegradable Chemicals
Hazards could not always be known or predicted： Chemicals: (resist biodegradation) exert toxic effect to biota (生物区), hardly to predict their potential toxic effect at the time of release to the environment. Moreover, bioaccumulative toxicity criteria (safe), but chronic (慢性的) or other unforeseen toxic effect (unknown). Increasing the safety of chemicals Increasing the treatability of the waste generated 四川大学化学学院
4.2.1 The Microbial Basis of biodegradation Animals: excretechemicals that they cannot metabolize; Plants: tend toconvertchemicals into water insoluble. Microbial populations: are characterized bycatabolic (代谢分解的) versatility,rapidgrowth in the presence of food, highmetabolic activity and species diversity. The eventualmineralizationof organic compounds (their conversion to inorganic substances such as CO2 and water) can be attributedpredominantly to microbialdegradation.
The key role in biodegradation: An abundance ofevidence existsto show thatmicroorganisms are responsible forthe degradation of many organic chemicals cannot be altered significantly by higher organism. Microorganisms（primarily bacteria 细菌 and fungi 真菌）are by far themost importantagents of biodegradation in nature.
Microbial degradation is the major loss mechanism for most organic chemicals in aquatic(水的) and terrestrial（陆地） environments, and is the cornerstone of the modern wastewater treatment plant. SCU 成都活水公园 四川大学化学学院
The process of biodegradation 1.An organic compound must first enter the microbial cell through the cell wall & cytoplasmic (细胞质) membrane.This may occur bypassive diffusionor with the assistance of specific transport systems. Especially: for aquatic and terrestrial (陆生的) environments ——low levelsof organic substrate and other nutrients. For example: large polymeric substrates: proteins, polysaccharides (多糖), biodegraded to smaller chemicals by extracellular enzymes (细胞外酶).
The process of biodegradation 2.Once inside the cell, the reactions that a compound may undergo are determined by its molecular structure, hundreds of transformations have been described in the literature, but almost all can be classified broadly as： • oxidative; • reductive; • hydrolytic; • conjugative reactions
The process of biodegradation What process a special compound will undergo inside the cell depends strongly on its molecular structure. In addition, The catabolic pathways employed by microbial populations are also diverse and vary with the environmental conditions. 四川大学化学学院
The strategy of microbial degradation But despite the immense structural variety of naturally occurring as well as anthropogenic (人类引起的) compounds, their utilization by microorganisms always involves the same basic strategy. That strategy isstepwise degradationto yield one or more intermediate products capable of entering the central pathways of metabolism. The overall objective is always to produce carbon and energy for growth.
The strategy of microbial degradation Persistent and toxic intermediatesoccasionally arise from potential biodegradation of a compound, but this is the exception rather than the rule. Naturally occurring organic compounds are degradable via pathways that represent evolutionary adaptations to prevailing conditions. 四川大学化学学院
Gratuitous metabolism （幸运代谢） Many man-made chemicals are identical or similar to naturally occurring substances, but human activities have also produced structures never seen or at least infrequently encountered in nature. Many of these, nonetheless, can be attacked by microorganism by virtue of a phenomena referred to asGratuitous Metabolism or Fortuitous Metabolism. Cause：degradative enzymes generally are not absolutely specific for their natural substances.
The Microbial Basis of Biodegradation Chemical Structure and Biodegradability Group Contribution Method for Predicting Biodegradability Examples of Designing Biodegradable Chemicals 四川大学化学学院
4.2.2 Relationship between chemical structure and bio-degradability The bio-degradability of a substance, which is one of the properties of the substance, depends strongly on its chemical structure. Studies, Research and Environmental Monitoring : Small changes in molecular structure can appreciably alter a chemical's susceptibility to biodegradation!
Relationship between chemical structure and bio-degradability The following molecular features generally increase resistance to aerobic biodegradation: • Halogens; especially chlorine and fluorine; • Chain branching（支链物质）, especially quaternary carbon（季碳）and tertiary nitrogen, or extensive branching such as in surfactants derived from tri-or tetrapropylene; • Nitro, nitroso（亚硝基）, azo（偶氮基）, arylamino groups（芳氨基）; 四川大学化学学院
Relationship between chemical structure and bio-degradability • Polycyclic residues（多环残基）(such as in polycyclic aromatic hydrocarbons（多环芳香烃）or PAHs（稠环芳烃）), especially with more than 3 fused rings; • Heterocyclic residues（杂环残基）; e.g., pyridine rings（吡啶环）; • Aliphatic ether (C-O-C) bonds（脂肪族醚键）. • High-substituted compounds.
The Cause for resistance to biodegradability For the most part, the features listed above affect the ability of the compound to serve as an inducer or substrate, or both, of degradative enzymes and cellular transport systems. For example, Addition of a chlorine atom to a phenyl ring makes the ring less susceptible to attack by oxygenase enzymes, which utilize a form of electrophilic oxygen as a cosubstrate (共存底物). Strongly electron-withdrawing (吸电子) substituents such as halogens are therefore to be avoided in chemical design if possible.
Note: This list is not exhaustive(详尽的), nor should it be inferred that the presence of even a single atom or group from the list necessarily renders a compound recalcitrant (反抗的). Moreover, in most cases the mechanism by which increased resistance to biodegradation is conferred is not known in detail. But this should not blind us to the fact that sufficient information is available to allow application of these principles in chemical design. 四川大学化学学院
The chemical structures which favor biodegradability Biodegradability is usually enhanced: • by the presence of potential sites of enzymatic hydrolysis (e.g., esters, amides); • by the introduction of oxygen in the form of hydroxyl (羟基), aldehydic (醛基) or carboxylic (羧基) groups; • by the presence of un-substituted linear alkyl chains (especially >4 carbons) and phenyl rings, which represent possible sites for attack by oxygenases.
The chemical structures which favor biodegradability The first step of biodegradation is some kind of oxidation reaction. And this step is almost always rate limiting. The second of these three factors is particularly important because the first step in the biodegradation of many compounds (e.g., hydrocarbons) is the enzymatic insertion of oxygen into the structure.
The importance of inserting oxygen in themolecule More generally, if the first biodegradative step is some form of oxidation, it seems logical to expect that biodegrability will be enhanced if the synthetic chemist has in effect already carried it (oxygen inserted) out during molecular design.
The solubility and bio-degradability The aqueous solubility of the molecules alter significantly the biodegradability. The possible effects of solubility on biodegradability are as the following：
The solubility and bio-degradability 1: Microbial bioavailability (微生物生物利用度) • Insoluble chemicals tend to adsorb in activated sludge (淤泥), sediments (沉积物) and soil (土壤). Most studies have shown that this tends to reduce the rate of biodegradation. • Under the same conditions, the inclusion of groups which increase the solubility of a insoluble chemical may increase its biodegradability.
The solubility and bio-degradability 2： Rate of solubilization (溶解速度) • Most studies have shown that for solid with very low solubility, only the dissolved or dispersed phase is available to microorganisms. • Therefore, the rate of dissolution of a solid in water may control the rate of biodegradation. • Many microorganisms excrete biosurfactants (e.g., rhamnolipids,鼠李糖脂) that enhance the rate of solubilizition.
The solubility and bio-degradability 3：Low aqueous concentration • Some studies have shown that for chemicals soluble to the extent of only a few micrograms per liter or less, this concentration may be too low for optimal function (无法发挥其最佳功能) of cellular enzymes (细胞酶) or transport systems (传输系统). Thus the biodegradability is limited.
The solubility and bio-degradability At the present it can be stated that : • (i) highly substituted structures are likely to be less rapidly biodegraded than much simpler compounds; and • (ii) for very insoluble chemicals, replacement of a given functional group with one that increases solubility may also result in enhanced biodegradability. 四川大学化学学院