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The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.

A series of bicyclic pyridine containing alkaloids related to (−)-cytisine and varenicline are described. Synthetic access via regioisomeric metalation of alkoxy- and halo-pyridines gains entry to all four isomeric [3.3.1]-bicyclic targets. Regioselective and sequential oxidative cleavage of dicyclopentadiene generates a related [3.2.1]-bicyclic analog.

Acute benthic toxicity tests can be a useful tool for screening nonaqueous base fluids used in drilling fluids. These toxicity tests were originally designed to evaluate dredged spoil, and were adapted and introduced as a standard benthic test, using field sediments for approval of nonaqueous drilling fluids, by the Oslo & Paris Commission (OSPAR) in the North Sea in 1994. In the US, development of a standard benthic test for regulatory approval of nonaqueous drilling fluids and screening new base fluids is continuing. There is now some concern that the variability and nature of field sediments can cause effects in addition to the toxicity of the test material. Use of formulated sediment to replace natural sediment may greatly decrease this variability, and allow for greater interlaboratory comparisons. The formulated sediment developed and refined in this study consisted of 30% sand, 20% silt, 48% clay, 1% organic material, and 1% calcium carbonate. This formulation produced acceptable control survival (>90%) in ten toxicity tests using Leptocheirus plumulosus. The results of five diesel toxicity tests and five C1618 internal olefins toxicity tests produced coefficient of variations of 16.0 and 28.9, respectively, indicating the formulation can produce consistent test results.

In 1996, during the development of synthetic-based drilling fluids as a pollution prevention technology, the need for an accurate and reliable sediment toxicity test was identified as a critical regulatory requirement. Using industry and U.S. Environmental Protection Agency (EPA) resources, a sediment toxicity test was rapidly developed and deployed to meet the regulatory requirements for end-of-pipe testing. In 2002, the implementation of the test as a routine requirement highlighted the need to understand and manage the issue of biological test variability within the context of a regulatory limit. This paper reviews over 100 split sample events that were conducted from 2005 to 2010 in order to develop information concerning the recognition and management of test variability. The experience developing and implementing a biological test over a 15-year period is also reviewed so that other areas of the world developing new tests and investigating potential laboratory capabilities can more fully appreciate the challenges of using biological tests for regulatory compliance.

A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.

John Candler (1787–1869), a Quaker Abolitionist, visited the West Indies between 1839 and 1841, to study the situation of ex-slaves since they had obtained their freedom. He spent three months in Haiti, and appears to have been generally impressed by what he found. The former slaves had become smallholders, growing crops on small plots of land, though they were not interested in producing more than they needed for their basic livelihood. The export of coffee, cotton and tobacco had declined since the end of slavery, and the sugar trade had ended. Whites were barred from owning land, or from marrying Haitians, and were restricted in trading activities, reducing available investment capital. The compensation demanded by France to the former plantation owners was also crippling the economic development of the island. Candler's book gives much valuable detail about an important former colony at a time of transition.

Shale drill cuttings exposed to synthetic-based drilling fluids (SBDF) processed by cuttings dryers were studied under simulated deepwater discharge conditions and found to size degrade with time. This hydration and size degradation is similar to what occurs with water-based cuttings. Lower retention on cuttings and wider dispersion of discharged cuttings results in lower organic enrichment, which reduces potential seafloor impacts from deepwater drilling operations. While this was indicated in previous studies, it had not been confirmed with laboratory studies that simulate deepwater conditions. Previous studies reported settling velocities after exposure to seawater for only a few minutes. A cutting may settle at speeds that allow exposure to seawater for 0.9 to 3 hours for each 3,280 ft (1,000 m) of water depth. A flow loop was constructed to expose cuttings to seawater for extended time periods and separate the cuttings into fractions of four different settling velocities. Changes in each fraction with increased time indicate changes in settling velocity distribution. The flow loop consists of a series of increasing larger clear vertical tubes where smaller particles carry over to larger lower velocity columns. An initial experiment with inert solids plus three different shale cuttings were tested. The concentration of synthetic on initial and final samples was measured and correlated to size. Video photography was used to document and characterize cuttings behavior. Current discharge models do not include the effect of size degradation on reduced fall velocity for deepwater discharges. Reduced fall velocity causes a wider aerial dispersion that reduces the potential for the formation of significant cuttings accumulation and reduced environmental impact. Accurate cuttings size is needed to determine a fall velocity and accurately predict the distribution of drill cuttings discharged into the ocean. Data from previous fall velocity studies and field monitoring studies will be presented and discussed.

The synthesis and structure–activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).

Environmental and health issues are frequently nettlesome and often costly if left unaddressed. Within the last 40 years many industrialized countries have developed laws for protecting citizen's health and the environment. These laws have helped in the development of regulations minimizing the impact of environmental and occupational health issues. Translated to the workplace, these regulations drive companies to develop programs with a structured and consistent approach that will protect its workers, minimize its impact on the environment, and protect communities in which it does business. The implementation of a management system provides both governances in an easy-to-use fashion. This constructive means of facilitating, fostering and encouraging performance has shown very dramatic results throughout an oilfield service company. In 2000, the firm developed a health, safety and environmental management system that included standards to which company operations would adhere. Since the company operates in a number of countries, the standards were written in a general nature to allow for incorporation of local requirements. Each company location throughout the world was charged with implementing the requirements of the management system and making the changes necessary to conform to the corporate management system and the local regulations. Within a year of implementing the management system, audits were scheduled and performed at company facilities to confirm implementation and provide suggestions for further improvement to the management system. A scoring system was used to compare progress made by different sites within the same geographical area as well as progress made by locations throughout the company. This paper examines the cultural shift, attitudinal redirection and resultant changes in the company's business activities in the occupational health and environmental sectors. This includes the integration of risk assessments and job safety analyses, emergency response planning and training, and annual auditing as tools to improve performance with the results from more than 50 countries over seven years charted.

The offshore oil and gas industry has moved toward the use of synthetic-based drilling fluids (SBF), changing potential exposure scenarios for discharged cuttings when compared to those of water-based drilling fluids (WBF). Unlike WBF, SBF sorbs predominately to particles in the cuttings and are not dispersed extensively into the water column, therefore, a sediment toxicity test was required by the US Environmental Protection Agency (US EPA) in addition to the existing water column test to define a best available technology (BAT) limit. Inclusion of a sediment toxicity test for NPDES compliance was precedent setting and unique. In order to fulfill the US EPA requirements, an inter-industry research group worked with EPA to develop a suitable test that met the technology-based discharge standard. Toxicity of discharged field drilling fluid is compared to a reference SBF (C1618 internal olefin) and, for compliance, the ratio of the reference drilling fluid median lethal concentration (LC50) to the field mud LC50 must be ≤1.0. Prior to its use, there were concerns that false positive results could cause incorrectly identified non-compliance events, limiting the use of SBF technology. Consequently, initial application allowed the use of a variability (K) factor in determining the ratio. After initiation as a compliance test, research was continued to reduce test variability and minimize false positives. That research included: 1) analysis of NPDES compliance data (500+ tests), 2) two inter-laboratory testing programs, 3) analysis of reference fluid data from one commercial laboratory, and 4) refinements to test sediment type and animal health. The results of these efforts to date are reviewed in this paper and are used to identify potential improvements in the application of the test as a regulatory tool.

Synthetic-based drilling fluids (SBF) have been used in a variety of drilling applications and are an important component of deepwater drilling operations. One of the applications of SBF is high-temperature wells. In order to address regulatory concerns about SBF in high temperature applications, an inter-industry study was conducted to examine the effects of temperature and time on the sediment toxicity (to Leptocheirus plumulosus) of synthetic-based fluids used for high-temperature wells. Four factors were examined: (1) ester content, (2) time, (3) temperature, and (4) alkalinity (absence or presence of green cement). Three base-stock fluids were tested, a 100% internal olefin (C1618 IO) and two traditional ester/olefin blends (10%/90% and 30%/70%). The base fluids were blended into drilling fluids and subjected to temperatures ranging from 275 to 350°F and time of exposures to temperature ranging from 16 to 160 hr. Phase 1 toxicity results indicated that temperature and time parameters bracketed the region where ester/olefin drilling fluids transitioned from passing to failing the sediment toxicity limitation. Phase 2 used a statistical experimental design to identify significant factors impacting toxicity, and a statistical model was developed to predict sediment toxicity ratios (STR). 2-Ethyl hexanol, an indicator of ester hydrolysis, was positively correlated with increased STR and could be used to screen for potential sediment toxicity. The sediment toxicity tests, analytical measurements, and the statistical STR model supported the hypothesis that, for the types of muds studied, toxicity increased for ester/olefin blends under downhole conditions of increased time and temperature. The data from this study support caution in the use of drilling fluids containing the type of esters (traditional esters) used in this study when temperatures exceed a threshold of ~300°F. Above 300°F, these materials may break down and result in increased sediment toxicity for the drilling fluids.

The key elimination step for the formation of 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity. 6Li and 13C NMR spectroscopic studies on 2-chloro-6-fluorophenyllithium reveal a single monomeric aryllithium, suggested by DFT computational studies to be a trisolvate. Rate studies indicate that the elimination of LiCl and LiF proceeds via trisolvated and disolvated monomers, respectively.

Noncoordinating solvents permit the halogen−metal exchange-induced formation of benzyne (aryne) from di- and trihalobenzene precursors in the presence of cyclopentadiene to give 1,4-dihydro-1,4-methano-naphthalenes. Studies with mixed halide precursors and nonacidic Diels−Alder diene traps reveal that ethereal and hydrocarbon solvents influence the halide leaving group facility, resulting in a reversal of 3-halobenzyne regioselectivity.

Since the introduction of synthetic-based mud (SBM) technology in the Gulf of Mexico, stakeholders have worked toward realization of the pollution-prevention aspects of SBM technology without losing the benefits of enhanced drilling performance. In addressing the issues of SBM in the Coastal Effluent Limitation Guidelines, the U.S. Environmental Protection Agency (EPA) recognized the pollution-prevention potential for SBM technology, but also determined that the exiting test protocols needed to be improved to measure environmental performance. In response to the Coastal Effluent Limitation Guidelines, industry work groups, including EPA scientists and engineers, took on the specific tasks of identifying and modifying test protocols that would allow continued positive development of SBM technology. The resulting test protocols for biodegradation, toxicity and analytical chemistry as described in the Effluent Limitation Guidelines for SBM technology will form the structure for usage of existing non-aqueous fluids and development of new fluids and fluid blends. This paper details the process of protocol and regulatory development, which is a success story applicable to other regulatory arenas and other issues in the U.S. The resulting regulatory framework and technology will lead to U.S. offshore operations becoming the hot bed of pollution prevention in the global offshore drilling community. The authors will show how continued use of SBM technology in the Gulf of Mexico will allow successful development of deepwater petroleum resources in an environmentally responsible manner.

The inability to consistently discriminate biodegradation performance inhibits the development and use of Synthetic-Based Muds (SBMs) and other non-aqueous base fluids. Government regulators and industry representatives are discussing and seeking to improve the repeatability, discriminatory power and environmental relevance of the current bottle and simulated seabed biodegradation tests. To date, the existing protocols and procedures are only moderately successful in discriminating the performance of various base fluids. This study provides information on the modification and development of an existing freshwater anaerobic test (ISO/DIS 11734)1 for use as a marine sediment anaerobic biodegradation test. This paper reviews and compares the repeatability, discriminatory power, practicality and ecological relevance of the modified test relative to the performance of other biodegradation tests and field data.

The use of synthetic-based muds (SBMs) can improve drilling performance and reduce the volume of pollution generated by offshore drilling operations. Investigations into the environmental impact of SBMs to date have concentrated on the seafloor. The biodegradation rate of an SBM is an important factor in determining the overall environmental performance. Laboratory biodegradation tests are an inexpensive alternative to conducting field studies. However, most of the tests have been designed for water-soluble compounds and reproducible results are difficult to obtain with regularity for hydrophobic materials like SBMs. For this study, a variety of base fluids were tested using the SOAEFD (Scottish Office of Agriculture, Environment and Fisheries Department) solid-phase test. This paper will evaluate SOAEFD solid-phase test results against other biodegradation protocols using a set of criteria designed to identify the best biodegradation test for SBMs.

Abstract The introduction of synthetic-based drilling fluids has challenged both industry and the Environmental Protection Agency to investigate benthic toxicity testing. The need for a synthetic-based mud screening tool has been highlighted by the call for benthic testing to be included into offshore general permits by Coastal Effluent Limitation Guidelines. Outside of the oilfield, development of solid phase testing of dredged material has led to standardized benthic testing protocols accepted by the Agency. ASTM E1367-92, used with Ampelisca abdita and Corophium volutator on sediments spiked with various base fluids, was able to distinguish synthetic-based muds from oil-based muds. It is demonstrated in this paper that analysis of other test species using ASTM El 367-92, and additional testing with A. abdita, can lead to rapid development of a benthic screening tool for incorporation into the next round of offshore general permits. This should promote the continued positive development of synthetic-based drilling fluid technology. Introduction The development and use of synthetic-based muds (SBMs) has resulted in significant advances in pollution prevention efforts for offshore drilling. The introduction of synthetic-based muds has challenged both industry and the Agency to look closely at existing test methods used in the regulation of mud and cuttings discharges offshore. The results of this study show that ASTM E-1367–92 with A. abdita is useful as a screening tool for SBM on the basis that the lower 95% confidence interval (CI) of the synthetic-based fluids was above the upper 95% CI of the diesel oil-based fluid. Continued development of ASTM E1367–92 using A. abdita, combined with investigation of other test species and protocols using the test analysis criteria described in this study, will lead to rapid development of a screening test for synthetic-based muds that will be acceptable to both the Agency and industry. Development of a Benthic Toxicity Screening Test for Synthetic-Based Muds. Identification of a standardized protocol and test species that would be easily recognized by the EPA was a prime consideration. By using recognized test species and protocol much of the groundwork for meeting the criteria for a screening test would be addressed and validated allowing for rapid development and implementation of a benthic screening test for synthetic-based muds. From the currently available standardized protocols, this study would seek to identity a test that would be reproducible, sensitive to the materials tested and discriminate among potential benthic toxicities of various base fluids. An additional goal was the identification of a species that would have ecological relevance to the discharge environment and could be subject to field validation. Two recognized test protocols were closely examined ASTM E1367–923 (EPA/600/R-94/025) (Amphipods) and ASTM E1611–94 (Polychactous Annelids). The ASTM E1367–2 protocol was chosen as focus of this study. Species included in the test protocol are listed in Table 1. In addition to literature available on the various test species, data available from a field study of a SBM discharge site at North Padre Island Block 895 (NPI-895) was used to select the test protocol and species for this study. When the mysid shrimp test was introduced, industry had considerable difficulty accepting the mysid shrimp test as a regulatory tool. Some of the key industry concerns that were identified were:–lack of validation of the test protocol;–lack of availability of the test species;–lack of purity in the test species; P. 63^

Deepwater drilling in the Gulf of Mexico is a challenging opportunity for drilling fluid performance. Synthetic-based muds (SBMs) applied in the Gulf of Mexico have overcome performance shortfalls of currently available water-based and oil-based muds. This paper will compare environmental, health, and drilling performance factors of polyalphaolefins (PAO) and internal olefins (10) SBMs with emphasis on rheological profiles, acute toxicity, benthic toxicity, bioaccumulation, and biodegradation rates. Field case histories of PAO and 10 SBMs used in deepwater projects are compared to water-based muds (WBM) and oil-based muds (OBM).

Summary Drilling fluids are now classified as exempt under the Resource Conservation and Recovery Act (RCRA) hazardous waste laws. Since 1986, however, the U.S. Environmental Protection Agency (EPA) has been studying reserve pit coutents to determine whether oilfield wastes should continue under this exemption. Concerns regarding reserve pit contents and disposal practices have resulted in state and local governmental regulations that limit traditional methods of construction, closure, and disposal of reserve pit sludge and water. A great deal of attention and study has been focused on drilling fluids that eventully reside in reserve pits. In-house studies show that waste from water-based drilling fluids plays a limited role (if any) in possible hazards associated with reserve pits. Reserve pit water samples and pit sludge were analyzed and collated. Analyses show that water-soluble heavy meta1s (Cr, Pb, Zn, and Mn) in reserve pits are generally undetectable or, if found in the total analysis, are usually bound to clays or organics too tightly to exceed the limitations as determined by the EPA toxicity leachate test. Our experience is that most contamination associated with reserve pits involves high salt content from produced waters and/or salt formations, lead contamination from pipe dope, or poorly designed pits, which could allow washouts into surface waters or seepage into groundwater sources. Our analyses show that reserve pits associated with water-based drilling fluid operations should not be classified as hazards; however, careful attention should be paid to reserve pit construction and closure to help avoid any adverse environmental Impact. Introduction Oil and gas drilling activities produce wastes that need to be disposed of in a manner that is both economical and safe for the environment. The traditional method of disposal has been to discharge wastes into a reserve pit located at the drill site. Upon completing the well, the pit waste can be dewatered and then filled, solidified, or treated in any number of ways on location or the waste can be removed for offsite disposal.1 The most economical method is to backfill the pit on site. State and federal agencies, however, have recently questioned this practice. Many states have passed laws regulating pit construction and closure,2 and in 1986 the federal government began a study to characterize reserve pit waste constituents to determine whether oilfield waste should remain an exempt waste under the federal hazardous waste laws.3 With this situation in mind, we decided to investigate reserve pit constituents containing waste from water-based driling operations. Chemical analyses were conducted on reserve pits shortly after drilling operations were completed. Results were collected and collated to determine the range of inorganic constituents present, and concentration of metals and ions were compared to various water-quality parameters to determine whether these levels would be considered a hazard to the environment or to humans. Literature Review Few studies are available that investigate the effects of reserve pits on soil, groundwater, or plant productivity. Miller4 summarized studies conducted since 1974 that were sponsored by the American Petroleum Inst. (API). Results indicated that some common constituents of drilling fluids can affect plant growth, but these effects can be reduced or eliminated by proper soil application. The two most detrimental constituents werehigh sodium levels, which resulted in hard soil crusts, andsoluble salts, which made water absorption by plants difficult. Diesel used as a lubricant in some drilling fluids did show phytotoxic effects (inhibiting germination and/or killing seedlings) and also reduced soil wettability. Alkaline muds (high in sodium salts) caused the least problem in acidic soils having a high organic-matter content. The most difficult problem occurred when alkaline muds were added to alkaline soils in areas with low rainfall. Suggesed reclamation procedures includedaiding soluble calcium salts or gypsum.adding water, orallowing enough time for microbial decomposition. Moseley5 summarized three other studies funded by API that substantiated Miller's work. Heavy metals from reserve pits were found to migrate slowly and were below standards set by the EPA for hazardous wastes. Some plants can and do take up heavy metals, but not at high levels and not at concentrations that can endanger wildlife.5 Nelson et al.6 postulated that low-grade barite might be one of the major sources of trace metals in soils. However, soluble levels of low-grade barite in the soil and uptake by plants, even in greenhouse pot studies, were minimal. All these studies agreed that mixtures of 1:4 mud to soil were adequate to safeguard the environment and groundwater sources. Younkin and Johnson7 discussed the methods and effects of drilling waste-soil disposal in Canada. Their findings also showed that high-salt muds (KCl systems) caused the highest amount of damage to the natural plant cover, seed germination, and productivity. Salt content above 34,000 ppm was damaging to plant health and soil chemistry. Diesel fuel at or below 4,500 ppm had only a slight effect on plants, while lignosulfonate (165 ppm or less) and polymers (67,000 ppm or less) had little effect. No long-term-effects were noted for any of the reserve pits investigated and no damage was evident after 3 years. Mikesell8 found that muds added to soils increased the total concentrations of zinc, copper, lead, chromium, and barium, but the metals were in a form that was not available for plant uptake. Murphy and Kehew9 found that shallow groundwater obtained from the unsaturated zone beneath reserve pits exceeded the recommended concentration limits for trace elements and major ions; however, levels were greatly reduced as the depth increased. The reduced levels beyond the immediate area of the pit suggested that very little impact was expected on usable groundwater resources. Methods and Materials As waste settles in a reserve pit, it splits into a water phase and a sludge phase, which is called the mud phase. Samples were collected from both the water and mud phases from 125 reserve pits dating from 1979 through 1986. The majority of the samples were from reserve pits located in west Texas, Oklahoma, and Louisiana. Samples were also collected in California and the Rocky Mountain states.

Dialectics relates to the process of reasoning from probabilities and observed indications. The scientific method reasons from meticulously stated data presented so that another mind can analyze and evaluate the accuracy, force, and effect of each datum. The dialectic method precedes the scientific. The dialectic method precedes the scientific. The dialectic method is necessary in the treatment of problems that must be acted upon but which have not been conclusively analyzed by scientific methods. This method does not add to the fund of human knowledge. An example of the dialectic method is the report on "Parole and the Indeterminate Sentence" made in Illinois. The scientific analysis of social science phenomena includes four methods: statistical, case study, observation, and experimentation. There are no "statistical data": a datum is a fact or assumption; statistics, classification and presentation. A case study may be classed as experiment which, if properly controlled, would produce dependable results...

In an article published last year I said, "It cannot be stated as a fact that there is any sociological or economic problem which cannot be solved by quantitative methods." This statement has been criticized and a number of problems cited as not susceptible of quantitative treatment. An analysis of the underlying content shows that in each instance the problems presented contain two or more fundamentally differing elements which are not clearly stated and defined. A problem containing several different elements is several problems, and an attempt to solve several problems jointly leads to inextricable confusion. A concrete example is offered, "tariff protection versus free trade." This problem has been discussed for a century; the content has never been stated nor the terms used clearly defined. The interminable discussion of it has led around in circles, because it is an imporperly stated and undefined composite problem. Its elements can be restated as separate problems with prospect of solution. Scienti...