04 第四章 设计更加安全化学品的应用.ppt

第1页：第四章 设计方法的应用

Chapter 4 Application of Designing Safer Chemicals

第2页：第四章 章节导航

• 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 Aquatic ally Safer Chemicals
• References

第3页：4.1 硅对碳的等排置换

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

第4页：硅是碳的等排体

Silicon is an Isos tere of Carbon Differencesbetween Siliconcompounds and Carbon compounds The degradation and oxidative metabolism of organic silicon compounds Examples of

第5页：4.1.1 硅与碳的共同点

4.1.1 Silicon is an Isosteric atom of Carbon Common Features of Silicon and Carbon

• grouped in column 4 Aof the Periodic Table
• having many chemical similarities：tetra valent, tetrahedral, and form stable bonds with carbon.
• 金刚石碳化硅

第6页：有机硅衍生物的低毒性

4.1.1 Silicon is an Isosteric atom of Carbon Organic derivatives of silicon and carbon generally have no intrinsic toxicity, in contrast with the other Group 4 A elements germanium, tin, and lead. Fro

第7页：有机硅化合物的寿命

The lifetime of organic silicon compounds is quite limited Insecticide (杀虫剂) Example Urethane s(尿烷), neutral analogs of the neuro-transmitter(神经传递质)acetylcholine(乙酰胆碱)(1), were found to be antagonists

第8页：乙酰胆碱与尿烷

Acetylcholine(乙酰胆碱) Urethane(尿烷) Musca rini c Antagonist is（蝇覃碱拮抗剂）

第9页：氨基甲酸酯的硅等排体

Carbamate Silicon substituted Isos tere of carbamate(More de grad able, less toxic to human and environment) Carbamate insecticide and its silicon analog were found to have similar toxicity to the hou

第10页：叔丁基与三甲基硅基

• In both of these examples, the tert-but yl and tri methyl sil yl groups function simply as isos tere s of tri methyl ammonium.

第11页：硅取代的局限

Silicon is the element most similar to carbon, however it is not a generic(属的)replacement for all carbon atoms and certain strict limitations apply. Double bonds to silicon, and three-membered rings c

第12页：硅氢键的极化

The silicon-hydrogen bond is more polarized than the carbon-hydrogen bond. Polarization: Si－H > C－HIn contrast to the carbon case, increasing the number of hydrogen on a silicon increases the ease of

第13页：聚乙烯硅烷与聚乙烯

[Si H 2－CH 2－CH 2－Si H 2－CH 2－Si H 2－CH 2]n Polyvinyl si lane: Stable H 2 C=CH 2 Ethylene: Stable H 2 Si=CH 2 vinyls i lane:unstable[CH 2 CH 2 CH 2 CH 2 CH 2 CH 2]n Polyethylene: Stable

第14页：原子尺寸与反应性差异

A subtle yet influential difference in atomic size exists for silicon and carbon , Important differences in chemical reactivity also exist. When silicon is proxima l(最接近的) to unsaturation, as in a vin

第15页：有机硅的降解途径

第16页：降解与氧化代谢

Abiotic Degradation Biological Oxidation 4.1.3 The degradation and oxidative metabolism of organic silicon compound An important component of designing safer chemicals is predicting their environment

第17页：有机硅的环境来源

Abiotic Degradation

• Currently the major environmental source of organ osi lane is silicone polymer(silo x an es), primarily polymers of 1,1-dimethyl si lane diol.
• Silo x an es were once thought to be environmentally stable, but are no known to de polymer ize in the presence of water and soil

第18页：甲基的光化学裂解

Abiotic Degradation

• Furthermore labeling studies have shown that the methyl groups can be photo-chemically cleaved from the silicon, with the final product being the naturally occurring silicates

第19页：硅氧烷的解聚

Silicone polymer (Silo x an es,聚硅酮) Depolymerizesinthepresenceofwaterandsoil Tosilicatesfinally

第20页：生物氧化的早期研究

Biological Oxidation

• Early studies of microbial growth in the presence of per methyl silo x an es suggested that biological cleavage of silicon-carbon bonds could occur
• More recent work has shown that microorganisms can utilize dime thy silo x an es as a source of carbon, and soil incubation(熟虑) of 14 C labeled silo x an es has been found to release 14 CO 2

第21页：哺乳动物的代谢研究

Biological Oxidation

• Pioneering work by Fessenden on the metabolism of organ osi lanes by mammals found that phenyl and alkyl si lanes were oxidized very much like their carbon analogs.
• A notable difference, however, was found for dimethyl phenyl si lane in which the silicon-hydrogen bond was rapidly oxidized in vivo

第22页：有机硅代谢研究

第23页：4.1.4 设计实例

Example 1：Si lane Analogs of DDT Example 2：Organ osi lane Fungicides 4.1.4 Examples for the Design of Safer Chemicals Using Silicon Substitution for Carbon

第24页：DDT 的硅类似物

Si lane Analogs of DDT

• Despite the relative safety of DDT to mammals, its toxicity to other species and environmental persistence led to the ban(被禁止) of this important pesticide.
• In an early effort to design a more benign version of DDT, a number of si lane analogs such as the DDD analog were prepared with the anticipation that these would be less environmentally persistent.
• While this would undoubtedly be true, all of the si lanes proved to be nontoxic to insects.

第25页：硅氢键的不稳定性

Si lane Analogs of DDT

• The presence of the readily oxidized silicon-hydrogen bond would have been one source of instability, both environmentally 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 con gene rs(同类的)

第26页：DDT 硅类似物复页

Si lane Analogs of DDT

第27页：有机硅杀菌剂

Organ osi lane Fungicides

• As a novel entry into the class of t riaz ole（三唑）fungicides（防真菌剂）
• M oberg and coworkers prepared a series of si lane analogs. One of these, flu sila z ole（氟苯代硅三唑）proved to be a highly effective crop fungicide（谷类防真菌）and is now a major commercial product.
• Compound flu sila z ole is an inhibitor of ster ol（固醇）biosynthesis, similar to other t riaz ole fungicides.
• The properties of this compound responsible for its field performance, including volatility, solubility, and movement within plants, have been described.

第28页：氟硅唑的代谢

Organ osi lane Fungicides

• The primary meta boli te of flu sila z ole is the sila no l,resulting from cleavage of the t riaz ole-substituted methyl group from silicon.
• Presumably sila no l has little or no biological activity, and the higher oxidation level sila no l will enhance the rate of its further degradation (relative to flu sila z ole).
• Flu sila z ole is an excellent example of the commercial potential for biologically active organ osi lanes.

第29页：氟硅唑的用途与代谢

Flu sila z ole （氟苯代硅三唑）Metabolism Usage：crop fungicide

第30页：第四章 章节导航

• 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 Aquatic ally Safer Chemicals
• References

第31页：4.2 可生物降解化学品设计

4.2 Designing Biodegradable Chemicals

第32页：可降解设计的内容

Examples of Designing Biodegradable Chemicals The Microbial Basis of Bio degradation Chemical Structure and Bio de grad ability Group Contribution Method for Predicting Biodegradability

第33页：分子设计的目标

If the safer chemical eliminates the production and release of more persistent and potentially hazardous substitutes. molecular design to enhance bio de grad ability to non-toxic products is pollution

第34页：危害难以预测

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 environm

第35页：可降解设计引言

第36页：微生物降解的作用

第37页：4.2.1 微生物基础

4.2.1 The Microbial Basis of biodegradation The key role in biodegradation: Microorganisms（primarily bacteria 细菌 and fungi 真菌）are by far the most important agents of biodegradation in nature, in terms

第38页：动植物的作用对比

The key role in bio degradation Animals:excretechemicalsthattheycannotmetabolize; Plants:tendtoconvertchemicalsintowaterinsoluble. Microbial populations:are characterized by cat a boli c(代谢分解的)versati

第39页：生物降解过程一

The process of biodegradation 1. An organic compound must first enter the microbial cell through the cell wall & cytoplasmic membrane.(This may occur by passive diffusion or with the assistance of spe

第40页：生物降解过程二

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;
• hydro ly tic;
• conjugative reactions

第41页：降解途径与结构

The process of bio degradation What process a special compound will undergo inside the cell depends strongly on its molecular structure. In addition The cat a boli c pathways employed by microbial pop

第42页：微生物的降解策略

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

第43页：持久性有毒中间体

The strategy of microbial degradation Persistent and toxic intermediates occasionally arise from potential biodegradation of a

第44页：巧合代谢

Gratuitous metabolism（幸运代谢）Manymanmadechemicalsareidenticalorsimilartonaturallyoccurringsubstances,buthumanactivitieshavealsoproducedstructuresneverseenoratleastinfrequentlyencounteredinnature. Many o

第45页：4.2.2 结构与降解性

4.2.2 Relationship between chemical structure and bio-de grad ability The bio-de grad ability of a substance, which is one ofthe properties of the substance, depends strongly

第46页：阻碍好氧降解的特征

• 1. Halogens;especially chlorine and fluorine;
• 2. 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 tetra propylene;
• 3. Nitro, nitro so（亚硝基）, azo（偶氮基）, ary l amino groups（芳氨基）;

第47页：多环残基与稠环芳烃

• 4. Polycyclic residues（多环残基）(such as in polycyclic aromatic hydrocarbons（多环芳香烃）or
• 5. PAHs（稠环芳烃）), especially with more than 3 fused rings;
• 6. Heterocyclic residues（杂环残基）; e.g., pyr i dine rings（吡啶环）;
• 7. Aliphatic ether (C-O-C) bonds（脂肪族醚键）

第48页：抗性产生的原因

The Cause for resistance to bio de grad ability For the most part, the features listed above affect the ability of the compound to serve as an induce r or

第49页：注意：非绝对判据

Note This list is not exhaustive, 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

第50页：促进降解的结构

• 1. bythe presence of potential sites of enzymatic hydrolysis (e.g., esters, amides);
• 2. bythe introduction of oxygen in the form of hydroxyl(羟基), al de hy dic (醛基) or carboxylic(羧基) acid groups;
• 3. by the presence of un-substituted linear alkyl chains(especially >4 carbons) and phenyl rings, which represent possible sites for attack by oxygen as es.

第51页：氧化作为第一步

The chemical structures which favor bio de grad ability The first step of biodegradation is some kind of oxidation reaction. The second of these three factors is particularly important because the fir

第52页：分子中引入氧

The importance of inserting oxygen in the molecule More generally, if the first bio de gra dative step is some form of oxidation, it seems logical to expect that bio de gr ability will be enhanced if

第53页：取代基数目与溶解度

The solubility and bio-de grad ability The number of substituted groups attached to the main structure of the molecule and the aqueous solubility of the molecules alter significantly the biodegradabil

第54页：微生物生物利用度

1: Microbial bio availability (微生物生物利用度) Insoluble chemicals tend to partition to the ads or bed state in activated sludge, sediments and soil. Most studies have shown that this tends to reduce the ra

第55页：溶解速率

The solubility and bio-de grad ability 2：Rate of so lub i liz ation (溶解速度)Moststudieshaveshownthatforsolidwithverylowsolubility,onlythedissolvedordispersedphaseisavailabletomicroorganisms.Therefore,

第56页：低水相浓度

The solubility and bio-de grad ability 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 b

第57页：两条经验结论

The solubility and bio-de grad ability At the present it can be stated that

• (i) highly substituted structures are likely to be less rapidly bio degraded 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.

第58页：4.2.3 基团贡献法

4.2.3 Group Contribution Method for Predicting Bio de grad ability What is the essence of Group Contribution Method ??????Question

第59页：基团贡献法的前提

Group Contribution Method for Predicting Biodegradability

• The basic premise is that the activity of interest is a function of the contribution of one or more molecular substructures or fragments of which the molecule is composed, and that the contribution of each fragment does not vary from compound to compound (i.e., there is no interaction between fragments).
• The ideal situation is that each fragment in a model has a clear mechanistic relationship to the activity of interest, which is understood at the molecular level.

第60页：模型的现实条件

Group Contribution Method for Predicting Biodegradability

• This situation is rarely if ever realized.
• Fortunately, it doesn't really matter as long as
• (i) there exists for model development a set of measured values ("training set") of adequate size, and
• (ii) a reasonably comprehensive set of structural fragments associated in some way with activity can be identified.

第61页：Boethling 的模型

4.2.3 Group Contribution Method for Predicting Bio de grad ability R. S. Boe th ling et al.used this approach to develop a set of 4 models for predicting biodegradability. Two of the models (based on

第62页：模型的分类用途

Two of the models (based on linear and nonlinear algorithms) classify chemicals as easily or not easily biodegradable,and the other two(for primary and ultimate biodegradation) make semi-quantitative

第63页：4.2.4 设计实例

4.2.4 Examplesof Designing Biologically Safer Chemicals

第64页：三类案例

Linear Alkyl benzene S ulf on at es(线性烷基苯磺酸, LAS）

• go D i alkyl Qua tern aries (二烷基季铵)
• go Alkyl phenol Eth oxy late s(烷基酚乙氧基化物, APES）
• Got able 4-1

第65页：案例1 线性烷基苯磺酸盐

1: Linear Alkyl benzene S ulf on at es（线性烷基苯磺酸, LAS）Soap 1940 The development of laundry detergents based on linear alkyl benzene s ulf on ate (LAS) is a brilliant success story, and a case can be mad

第66页：烷基链的来源演变

Linear Alkyl benzene S ulf on at es

• At first the alkyl chains were derived from a kerosene(煤油) fraction,
• but these products were soon replaced by ABS produced from propylene tetra mer.
• Tetra propylene alkyl benzene s ulf on ate (TPBS) was a more efficacious and economical product, obtained via a one-step Friedel-Crafts process involving addition of benzene at the double bond of the olefin feedstock to yield the branched alkyl benzene, followed by sul fo nation of the benzene ring.

第67页：TPBS 的典型结构

As manufactured TPBS is actually a complex mixture but a typical structure is continue What will happen with highly branched hydrocarbons ???

第68页：支化产品的环境问题

Environmental problem Environmental problems with these highly branched products appeared almost immediately, as they(TPBS)were found to be in completely

第69页：用线性LAS替代TPBS

Using linear Alkyl benzene S ulf on ate store place TPBS[TPBS] was degraded by only about 50 %in sewage treatment units and as a result excessive foaming occurred in activated sludge aeration (通风) tan

第70页：泡沫问题的严重性

How to solve this problem ???

• The foaming was far worse than that caused by protein a ceo us(蛋白质的,似蛋白质的) material in sewage prior tothe introduction of synthetic surfactants and in extreme cases sewage-works operators were killed by asphyxiation(窒息) after falling into foaming tanks from walkways made slippery by the foam...
• because of its incomplete biodegradation, the concentration of TPBS in river waters was as high as 2 mg L-1, and water tended to foam when coming out of the tap."

第71页：线性结构的改进

Using linear Alkyl benzene S ulf on at es(LAS) to replace TPBS: the ster uc ture Eventually methods were developed that permitted the economical manufacture of a more environmentally acceptable produc

第72页：案例2 二烷基季铵

2．Di alkyl Qua tern aries（二烷基季铵）Surface-active quaternary ammonium compounds(generally referred to as QACs or “quats”) first gained prominence（突出）more than 50 years ago, with Do mag k‘s discovery that

第73页：季铵盐的应用现状

Problems: There are still many QA C-type biocide s in use, but household fabri(避难所); softeners presently constitute the largest market by far for QACs. Other applications are mainly industrial and inc

第74页：三类主导产品

Di alkyl Qua tern aries According to Cross, 66 % of the market for QACs is dominated by three classes, all of which are di alkyl qua tern aries, meaning that hydrophobic it y(疏水性) is imparted（授予）to th

第75页：三类结构的比较

Problems: The three classes are di alkyl dimethyl ammonium salts, i mid a zo liu m quaternary ammonium salts, and eth oxy late d ethan a mini um quaternary un moni um salts, with typical structures sh

第76页：二烷基二甲基铵盐

1）di alkyl dimethyl ammonium salts（二烷二铵盐）continue

第77页：咪唑季铵盐

2) i mid a zo liu m quaternary ammonium salts（咪唑季铵盐）continue

第78页：羟乙基乙铵鎓季铵盐

3) eth oxy late d ethan a mini um quaternary un moni um salts（羟乙基乙铵翁季铵盐）

第79页：DHTDMAC 的应用

Di alkyl Qua tern aries

• Until recently the fabric softener market was dominated by a QAC of the first type, di hydrogenated tallow(动物脂) dimethyl ammonium chloride(DH TD MAC) The long alkyl groups in DH TD MAC are derived, as the name implies, from purified animal fat (tallow), and consist of a mixture chiefly in the C 16-C 18(tallow fatty acids) range.

第80页：DHTDMAC 的环境归趋

Di alkyl Qua tern aries

• The true aqueous solubility of DH TD MAC is exceedingly low, and the chemical sorbs strongly to solids in wastewater treatment and the environment. Removal in treatment is therefore high (> 95 %), unlike TPBS, but does not necessarily cones pond to ultimate biodegradation.

第81页：DHTDMAC 的环境争议

Di alkyl Qua tern aries

• More importantly, the heavy useof DH TD MAC before 1990, its relatively low rate of bio degradation in aquatic sediments, and its high intrinsic eco toxicity led to a public perception in some parts of the world, particularly Europe, that DH TD MAC was placing a critical load on surface waters.
• As a result DH TD MAC has been phased out of the European market, with consumption declining from a peak of about 50,000 metric tons per year before 1990 to 4,500-9,000 tons in 1993. Similar changes are occurring in the U. S.market as manufacturers are voluntarily reformulating their products.

第82页：替代产品的转向

DH TD MAC is being replaced by di alkyl QACs in the other two classes listed above, the i mid a zo liu m and eth oxy late d ethan a mini um QACs. Although the database on environmental fate and remova

第83页：新型柔顺剂的意义

• These new, more biodegradable fabric softening agents thus represent another illustration of how safer surfactants can be developed by rational molecular design.
• The approach here may appear to be different from that for TPBS/LAS since it involves direct incorporation of a molecular feature known to favor biodegradability(Table I), not the deletion of an impediment (branching) as in TPBS.

第84页：线性替代的实质

• But this distinction is really not very meaningful since the replacement of tetra propylene with a linear alkyl group in ABS/LAS also facilitates beta-oxidation by competent microorganisms. Attack on the alkyl group is in fact the principal degradation pathway for LAS QACs.

第85页：工业领域的延伸

• Until now discussion has been limited to chemicals used in high-volume consumer products, but the same principles can be applied to products used chiefly in industry.

第86页：EPA 预生产申报案例

A good example of appropriate technology is contained in a recent non-confidential PMN received by EPA. The notified chemical substance proposed for use as a textile fiber finish, is essentially the e

第87页：线性烯烃替代

第88页：线性替代未成规模

Butthesubstitutionoflinearforbranchedolefins,whichwouldlogicallyconstitutethenextstepintheevolutionofsafer APEs,has not occurred on a large scale. Theremaybevariousreasonsforthis,butthefactthatthestri

第89页：案例3 烷基酚乙氧基化物

3．Alkyl phenol Eth oxy late s（烷基酚乙氧基化物）Alkyl phenol eth oxy late s (APEs), are one of two major classes of non ionic surfactants（非离型表面活性剂）. A

第90页：APE 的工业用途

• In screen reclamation（改造）NPEs are used in ink, emulsion and haze removal formulations, according to EPA's draft Cleaner Technologies Substitutes Assessment (CTSA) for the screen reclamation use cluster.

第91页：APE 的支化特征

• Unlike linear alcohol eth oxy late s (乙氧基化物，the other major class of non ionic surfactants), APEs are mostly branched. The industrial synthesis

第92页：丙烯低聚体路线

These products long ago were replaced by APEs derived from propylene oli gomer s，which are structures without quaternary carbons but still containing

第93页：降解中间体的争议

Debate Most attention has focused onthe mono-and die th oxy late d non yl phenol adduct s NP 1 EO (n = 1) and NP 2 EO (n = 2),which have been reported to be relatively stable intermediates in NPE biod

第94页：降解中间体结构

第95页：低乙氧基物的毒性

• NP 1 E 0, NP 2 E 0 and non yl phenol itself are highly toxic to aquatic organisms, whereas the parent NPEs(the number of eth oxy late groups may be as high as 30-50, but 12-14 is more typical) are much less toxic.
• Recently added to this is a new controversy, as non yl phenol, NP 2 EO and related compounds have been reported to be estrogen ic(雌性激素的) in fish.

第96页：APE 降解率对比

APE% Bio degradation Linear Branched C 8 AEE 97146 C 8 APE 9：containing 9 oxy-ethyl group 5149 C 9 APE 96525 C 9 APE 9：containing 9 oxy-ethyl group 6530885557336632750621060180~5008975 Table 4-1 Degra

第97页：APE 降解率数据复页

APE% Bio degradation Linear Branched C 8 AEE 97146 C 8 APE 9：containing 9 oxy-ethyl group 5149 C 9 APE 96525 C 9 APE 9：containing 9 oxy-ethyl group 6530885557336632750621060180~5008975

第98页：安全裕度的争议

• The actual margins of safety under environmental conditions for the above effects are a subject of intense debate, but the current situation might not have arisen in the first place if APEs were manufactured mainly from linear olefin s.
• Branched APEs bio degrade initially by stepwise shortening of the poly eth oxy late hydro phil e one eth oxy late group at a time, and attack on the branched alkyl group does not seem to be a significant pathway.
• Substitution of a linear alkyl group would eliminate an impediment(妨碍) to biodegradation and provide another site for microbial attack, by analogy to TPBS and LAS. This should lead to faster bio degradation and make transient accumulation of toxic intermediates unlikely.

第99页：降解路线的转变

• Experimental data support this contention. Indeed, studies suggest that a fundamental shift in the principal route of breakdown occurs such that degradation by beta-oxidation of the alkyl group (not attack on the poly eth oxy late chain) now predominates.
• Note that the enhanced bio de grad ability of linear APEs is easily predicted because the molecule now contains an additional fragment positive for bio de grad ability that is not present in branched APEs, the linear terminal alkyl with >4 carbons.

第100页：工业中的其他机会

• Other opportunities for pollution prevention by molecular design exist in industry. Textile processing seems especially amenable to this because sur fact ants have many uses as anti stats（抗静电的）, dye leveling agents, lubricants, etc., and substantial volumes of wastewater that must be treated before being released are generated.
• An eth oxy late d ethan a mini um di alkyl QA C proposed for use as a fiber finish that illustrates appropriate molecular design for enhanced biodegradability has already been mentioned.

第101页：阻碍降解的反例

• An example of molecular design that hinders rather than improves biodegradability is furnished by a class of an ionic sur fact ants with general the following structure. In this structure, R 1, R 2 and R 3 consist of one or two long alkyl groups and any other R groups are H (M is the counter ion).
• This class of surfactants has been the subject of numerous PMNs over more than 10 years at EPA, and most but not all proposed uses have been in textile processing.
• In most of these PMNs and possibly all (it's not always possible to determine) the proposed source of alkyl groups has been tetra propylene, despite Swisher's admonition that "Polypropylene derivatives such as [TPBS] are obsolescent because of the exceptional biological stability of some of the components.

第102页：阴离子表面活性剂结构

第103页：磷酸酯表面活性剂

• Another example from EPA's PMN program is a group of alk\l phosphate surfactants (9) with similar uses as in the preceding example. Iso( cta decano l phosphate (structure 9, n = 10) is typical and contains a highly branched
• n > drop hobe.

第104页：磷酸酯的水解

第105页：富营养化的担忧

• Here the specific uses proposed and hydro l yz able phosphate group suggest an additional concern for eu troph i cation(超营养作用 5) potential.
• Whether this effect would ever be realized would of course depend onthe production volume, circumstances of release and other factors.
• Nevertheless, G le isberg has strongly recommended that phosphate inputs to surface waters be reduced significantly in the interest of environmental protection.

第106页：丙氧基引入的反例

• The last example of molecular design that hinders rather than enhances biodegradability is the incorporation of prop oxy late(丙氧基) groups into poly eth oxy late d non ionic surfactants.
• F. PA frequently receives PMNs for such compounds and no doubt many enter commerce eventually. Data on biodegradation of mixed ethylene oxide (EOV propylene oxide (PO) surfactants are very sparse in comparison to EO-only non ionic s, but there is clear evidence that PO groups markedly retard biodegradation.

第107页：功能与降解的取舍

• In designing such products the synthetic chemist is undoubtedly maximizing some functional property of the sur fact ant, since the incorporation of prop oxy late groups allows control over the hydrophobic it y of the final product.
• For example, low-foaming non ionic s can be prepared by capping poly-eth oxy late s with poly-oxy propylene groups.
• The trouble with this is that since biodegradation would otherwise proceed stepwise from the free EO end as noted above, terminating the EO chain with a PO function effectively prevents bio degradation or at least greatly lowers the rate. Thus we can be sure that rational design from an environmental safety viewpoint is not foremost in the chemist's mind.

第108页：第四章 章名复页

Chapter 4 Application of

第109页：4.3 水生安全化学品设计

4.3 Designing Aquatic ally Safer Chemicals

第110页：水生生物的生态作用

• Aquatic species have their own unique roles in ecosystems and are important for the subsistence of other species, including consumer and predator(食肉动物).
• Among other things, aquatic species comprise the components of food chains that lead to man.
• Green algae are the primary producers in aquatic ecosystems in that, through photosynthesis, they produce oxygen and synthesize carbohydrates and other foodstuffs. Toxic effects of Chemicals to Aqu q tic species

第111页：食物链的传递

• These substances are used by consumer species which in turn serve asthe food source for predator species, including fish. Fish in turn, serve asa food source for wild mammals, birds, and man.
• Chemicals that are toxic to aquatic species may therefore put an ecosystem at unreasonable risk of harm, and can lead to disruption of some food chains.
• The survival of terrestrial species, including humans, is at least partially dependent upon aquatic organisms.

第112页：两类致死效应

Toxic effects of Chemicals to Aqu q tic species

• There are two general types of chemical-induced lethal it y in aquatic organisms:non-specific(i.e.,narcosis), and specific.
• The majority of chemicals

第113页：特异性毒性

Toxic effects of Chemicals to Aqu q tic species

• Some have excess (or additional) toxicity due to a more specific mode of toxic action. Chemicals that are toxic

第114页：麻醉型毒性机理

Narcosis Toxicity The mechanistic basis of narcosis toxicity is the ability of a chemical to diffuse across the biological membranes of an aquatic organism (e.g., gills in fish) Once a high enough con

第115页：脂溶性与膜穿透

Narcosis Toxicity Because cellular membranes have a higher lipid content, they are more readily penetrated by non-polar, lipid-soluble chemicals than by lipid-insoluble polar chemicals. Thus, the rela

第116页：反应型毒性

specific or reactive toxicity In contrast to chemicals that are only toxic by narcosis,some chemicals are toxic to aquatic organisms as a result of a

第117页：预测水生毒性

Use of Structure-Activity Relationships to Predict Aquatic Toxicity Modificationof Physicochemical Propertiesand Structure Modificationof Chemical Structurevia Chemical Class

第118页：4.3.1 构效关系预测

4.3.1 Use of Structure-Activity Relationships to Predict Aquatic Toxicity

第119页：七十年代的认知转变

During the 1970 s it was realized that many industrial chemicals could cause significant toxic effects to humans and the environment. It was also realized that unlike the requirement for pre market ap

第120页：TSCA 化学品名录

The Act called for EPA to establish a list of chemicals already used in commerce, known as the TSCA Inventory. Section 5 of TSCA requires anyone who wishes to manufacture or import a chemical that is

第121页：九十天的审查时限

Under TSCA the Agency is allowed only 90 days to determine whether the new (PMN) chemical may or will present an unreasonable risk to human health or the environment. TSCA empowers the Agency to take

第122页：预生产申报的内容

TSCA requires as a minimum for Agency review that PMNs include chemical structure and identity, method of manufacture, production volume, use, disposal, and the identity and concentrations of any know

第123页：基于构效的评估

• In order to identify risks posed by new chemicals for which no data are available, and to do so under the strict time constraints prescribed by TSCA,
• the EPA bases many of its toxicity assessments on structure-activity relationships (SARs).

第124页：构效关系的定义

What is SARs ???SARs refer to the ability of a group of analogous chemicals to produce a particular biological effect, and the influence that the structural differences between the chemicals have on r

第125页：常用物化参数

对水生生物毒性的定量构效关系（Quantitative Struct are-Activity Relationships，简记为 QSARS）中，常用的物理性质有：辛醇—水分配系数（通常用对数表达为 log P）、水溶性、解离常数（p Ka）、分子量、胺氮百分数（Percent Amine Nitrogen）（不包括苯胺类及在 PH=7 时无碱性的胺，如酰胺脲素等）。

第126页：4.3.2 调整结构与性质

4.3.2 Adjusting the Structure and Physical Chemical Properties

第127页：辛醇水分配系数

Oct an ol-Water Partition Coefficient（log P 或 log Kow）The oct an ol-water Partition Coefficient is a term used to express a substance's lip oph ili city,. It is the ph sico chemistry property most f r

第128页：logP 与毒性的关系

For non ionic organic substance that only exhibit a narcotic mode of toxic action：

• log P≤5，its acute toxicity and chronic toxicity will increase exponentially with increasing lip oph ili city ；
• log P＞5，toxicity following acute exposure decreases exponentially because ; bio availability begins to decrease
• log P:5-8，only chronic toxicity following chronic expo sur r occurs.
• log P:≥8，toxicity seen during chronic exposures becomes essentially him existent。Oct an ol-Water Partition Coefficient（log P 或 log Kow）

第129页：不同类型物质的规律

• "Narcotic" chemicals such as aliphatic alcohols, chlorinated benzene s, ke ten es, disulfide s, and "reactive" chemicals such as a cry late s, and esters demonstrate acute aquatic toxicity up to log P of 6.
• However, some reactive chemicals, such as, aliphatic amines and surfactants that have log P values greater than 8 may still exhibit acute toxicity.
• On the other hand, chemicals with low log P values are not sufficiently lip o phil ic to enter the cellular membranes of aquatic organisms, and therefore, are not bio available and are of low toxicity.
• For example, chemicals with molecular weights of less than 200 dalton s and have a log P of 2 or lower have low toxicity to aquatic species, i.e., acute median lethal concentration (LC 50) values greater than 100 mg/L. Oct an ol-Water Partition Coefficient（log P 或 log Kow）

第130页：降低水生毒性的设计

For chemicals whose aquatic toxicity is due to narcosis, chronic and acute aquatic toxicity Chemistscanreducethepotentialforaquatictoxicitybydesigningchemicalssuchthattheywillhavemolecularweightsofles

第131页：水溶性的影响

Water Solubility As a general rule, chemicals having water solubility less than 1 ppb are essentially non-toxic to aquatic species due to low bio availability. For example, tertiary amyl alcohol 1 is

第132页：分子量的影响

Molecular Size and Weight.

• If the new chemical's molecular weight is increased, the chemical will be less toxic to aquatic organisms while holding all other factors constant.
• At a molecular weight of 1000 Dalton s, uptake will be negligible because the chemical will not diffuse across the respiratory membranes of aquatic organisms.
• Chemicals with minimum cross-section diameters greater than 10 nm are too large for passive diffusion and uptake through the respiratory membranes of aquatic organisms.

第133页：酞菁染料的案例

Neutral ph t halo cyan in e dyes(天然酞菁染料)

• minimum cross-sectional diameters >> 1 nm.
• low acute and chronic toxicity to aquatic organisms The Design Principle*to increase minimum cross-sectional diameters*to increase the molecule size

第134页：离子对

（4）Ion Pair

• Some chemical salts exist as strong ion pairs when an ion and its counter ion are associated strongly with one another.
• These chemicals dissociate weakly or not at all in water.
• Consequently, may have low water so lub ili ties and low aquatic toxicity

第135页：离子对的设计应用

If a soluble and charged chemical can be converted to a strong ion pair and still retain its usefulness in a use application, then the resulting substance will be less toxic to aquatic organisms.

• For example, some pesticides are formulated with either cationic or an ionic surfactants i.e., inert ingredients to increase their bio availability.
• If the same pesticides could be formulated with the cationic sur fact ant: an ionic sur fact ant strong ion pair (assuming a 1:1 ratio), then the toxicity of the sur fact ant(s), could be reduced more than 100-fold. Here the formation of a strong ion pair to disperse chemical pesticides result in a safer commercial product, as opposed to a sur fact ant/d is per sant that is toxic to aquatic organisms.

第136页：两性离子

（5）Z witter ions

• Z witter ions and are substances that contain positively and negatively charged groups
• Z witter ions generally have low toxicity to aquatic organisms, provided that the substance has balanced charges and does not have sur fact ant properties.
• In general, most z witter ions are not surfactants, and toxicity to fish and da ph nids is low.
• However, algal toxicity has been observed at less than 10 mg/L for some chemicals.

第137页：酸性蓝1号

酸性蓝 1 号

第138页：螯合作用

（6）Ch elation Ch elation is the process in which a metal cation becomes bound within an organic molecule. In ch elation, two or more polar electron-lon a ting atoms (e.g., oxygen, nitrogen, etc.) with

第139页：螯合与藻类毒性

毒性来源及消除

• Ch elation can also occur through sulfur atoms with the formation of a stable fotir-membered ring. Sub lances thai can che late poly valent metals are often toxic to algae in soft water situations because they deprive the algae of essential nutrient elements, e.g., Ca 2+, Mg 2+, or Fe 2+.
• Therefore, algal toxicity can be reduced if a chel at or is bound with a poly valent metal before exposure to algae takes place or if the chemical is released to surface waters which have moderate to high hardness.

第140页：4.3.3 分子修饰

4.3.3 Molecular Modification

第141页：麻醉与过量毒性

1、Narcosis and Excess Toxicity

• Examples of chemicals that are toxic by specific mechanisms include: electro phil es such a sep oxides, alkyl halides, a cry late s, and aldehyde s certain esters; di nitro benzene s; and thi ol s, to name a few.
• The electrophilic chemicals may combine covalently with nucleophile s located in receptors of intracellular macro i role cu les. This bonding results in a cellular change that is difficult to reverse, and result; in irreversible toxicity.

第142页：过量毒性

Excess Toxicity The aquatic toxicity of a chemical that is toxic from a specific mechanism is usually considerably greater than that predicted for the substance using a QSAR equation developed for che

第143页：结构修饰降低毒性

2、The toxicity of chemicals that are toxic by modification The toxicity of chemicals that are toxic by a specific mechanism can be decreased by making ruc t ural modifications that steric ally hinder

第144页：结构修饰案例

第145页：半致死浓度对比

96

• h LC 50=47 mg/L 96
• h LC 50＞1000 mg/Lp H=7 p H=7

第146页：染料的四类划分

• 3. Dyes Organic dyes may be divided into four groups :
• 1. non ionic (neutral dyes);
• 2. an ionic (negatively charged dyes or acid dyes);
• 3. amp hot eric (mixture of positive and negative charges on the same molecule);
• 4. cationic (positive charged)

第147页：带电染料的毒性规律

3、Dyes For dyes which are charged (an ionic, cationic, and amp hot eric), no correlation (QSAR) has been found between aquatic toxicity and physicochemical properties. Therefore, instead of using QSAR

第148页：非离子染料的设计

（1）Non ionic Dyes or Neutral Dyes The theory of narcosis and excess toxicity discussed in the preceding paragraphs also applies to neutral dyes. To design safer neutral dyes:

• a water solubility below 1 ppb;
• adding polar substituents (If a neutral dye is required to be soluble)

第149页：酸性染料的类型

Acid dyes described here are those dyes with one or more acid groups present（2）An ionic Dyes Common structures (discussed in a later category)

• An thr aquino nes, (蒽醌)
• Nap ht hol s（萘酚）,
• Di nitro benzene s（二硝基苯）.

第150页：阴离子染料的毒性

（2）An ionic Dyes Molecular weights <1000 dalton s:systemic toxicity was be observed Molecular weights less than 1000 dalton s: (mono-and di-acid dyes)show moderate toxicity toward fish, invertebrates,

第151页：阴离子染料的设计

The design of An ionic Dyes The best way to design mono-and di-acid dyes is to increase the molecular weight to more than 1000 dalton s. This results in reduced toxicity to fish nd invertebrates, rega

第152页：金属络合酸性染料

（3）Metal i zed Acid Dyes A metal i zed dye is a dye that is related to a metal. Frequently, iron, copper, cobalt, aluminum, nickel, chromium, and zinc are the metals associated with moralized These dy

第153页：金属络合染料结构

第154页：金属络合染料的设计

The design of Metal i zed Acid Dyes Increasing the molecular weight above 1000 alton s will usually decrease aquatic toxicity. In addition, chemists should use metals such as iron, copper, or zinc, an

第155页：阳离子染料

（4）Cationic Dyes Cationic dyes are a chemically diverse group of positively charged dyes ranging in molecular weight from 200 to greater than 1000 dalton. The positive charge may appear on a carbon, n

第156页：离域型阳离子染料

Delocalized(离域化) cationic dyes positive charge is not located on a particular atom, often as a result of conjugation between heteroatoms such as nitrogen. For Delocalized cationic dyes:

• Molecular weights >(=)1000 dalton s exhibit lower toxicity (inability to be taken up by aquatic organisms).
• Contain primary nitrogen are generally less toxic than those that contains secondary nitrogen s, which are less toxic than those that contain tertiary nitrogen s. To design delocalized cationic dyes :
• increase molecular weights to more than 1000 dalton s.
• limit the extent of substitution on the nitrogen s

第157页：定域型阳离子染料

For localized(定域化)cationic dyes:

• decreases in toxicity occur as the number of positive charges of the dye decreases and all other factors are held constant.
• have one positive charge per molecule are less toxic than localized cationic dyes that have two positive charges, and so forth. The Structure and Toxicity of Cationic

第158页：阳离子染料的设计

To design localized cationic dyes :limit the number of localized positive charges or redesigning the dye to be amp hot eric. In all, for cat ionic dyes : In principle, designing localized or delocaliz

第159页：两性染料

（5）Amp hot eric Dyes Amp hot eric dyes

• behave as an acid or a base,
• are often characterized by the presence of positive and negative charges within the same molecule The toxicity of amp hot eric dyes depends onthe ratio of cations to anions in the dye. If the ratio favors the anion, then the dye will have lower toxicity (i.e., nearer to the acid dyes).

第160页：引入羧酸基的效果

For example, the addition of a carboxylic acid group to an amp hot eric dye will reduce the toxicity to fish and da ph nids bout 10-fold.

第161页：染料设计原则小结

阴离子数大于阳离子数（电荷数）磺酸基优于羧酸基尽可能使分子量大于 1000 尽可能增大分子的最小横截直径课堂作业：总结设计对水生生物更加安全的染料化学品应遵循的原则

第162页：表面活性剂

4、Sur fact ants Sur fact ants:contain both hydrophobic and hydrophilic moieties, which enable the substances to form micelle s in water. Surfactants are toxic to aquatic species because they can disru

第163页：亲水疏水平衡

第164页：亲疏平衡与毒性

The relative to xico logical potency of a sur fact ant is dependent on balance between the hydrophobic component and the hydrophilic component. In general, toxicity is higher when the hydrophobic comp

第165页：熔点与自分散性

Sur fact ants with melting points of 35°C will be self-dispersing in warm water only(e.g.,50°C)andwillnotfunctionassurfactantsatenvironmentaltemperatures(20 C). Suchsurfactantswillgenerallynotbeacutel

第166页：自学内容

• 6. Organo-Metallic s
• 7. Inorganic Metallic s
• 5. Polya mini c Monomers 自学内容

第167页：参考文献

参考文献 1，Roger L. Garrett, Designing Safer Chem icl s。

Stephen C Devito and Roger L. Garrett.edited American Chemical Society, Washington, D. C.1996，22，Stephen C Devito, Designing Safer Chem icl s. Stephen C Devito and Roger L. Garrett.edited American Chemical Society, Washington, D. C.1996,16.3.王连生，韩塑暌，等编著，分子结构、性质与活性，化学工业出版社，1997.

第168页：第四章作业（上）

第四章作业

• 1. 由碳、硅元素的化学性质，试讨论用硅取代碳的可行性及硅取代物的优点？
• 2. 用辛醇-水分配系数表征有毒化学品毒性的一般准则是什么？
• 3. 除了辛醇-水分配系数，还有那些性质可以表征有毒化学品毒性？
• 4. 从分子量、分子体积角度看，应该怎样设计更加安全的化学品？

第169页：第四章作业（下）

第四章作业

• 5. 可降解的化合物在化学结构和物理性质上有何特点？
• 6. 常见可降解和不可降解的基团有哪些？
• 7. 根据染料的基团特性，有机染料可分为几类？设计对水生生物更加安全的染料化学品要遵循怎样的原则？