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121-570: Although GenX was designed to be less persistent in the environment compared to PFOA, it has proven to be a "regrettable substitute". Its effects may be equally harmful or even more detrimental than those of the chemical it was meant to replace. GenX is one of many synthetic organofluorine compounds collectively known as per- and polyfluoroalkyl substances (PFASs). The chemicals are used in products such as food packaging , paints, cleaning products, non-stick coatings, outdoor fabrics and firefighting foam . The chemicals are manufactured by Chemours ,

242-671: A corporate spin-off of DuPont , in Fayetteville, North Carolina . GenX chemicals are used as replacements for PFOA for manufacturing fluoropolymers such as Teflon , the GenX chemicals serve as surfactants and processing aids in the fluoropolymer production process to lower the surface tension allowing the polymer particles to grow larger. The GenX chemicals are then removed from the final polymer by chemical treatment and heating. The manufacturing process combines two molecules of hexafluoropropylene oxide (HFPO) to form HFPO-DA. HFPO-DA

363-497: A 4.2-magnitude earthquake occurred on Saturday, May 2, 2015, shortly after noon, about five miles south of Galesburg, Michigan (9 miles southeast of Kalamazoo ) in central Michigan, about 140 miles west of Detroit, according to the Colorado-based U.S. Geological Survey 's National Earthquake Information Center . No major damage or injuries were reported, according to then-Governor Rick Snyder 's office. State government

484-461: A consent order. The order signed by all 3 parties requires Chemours drastically reduce PFAS containing water discharges and air emissions, as well as sampling and filtration for well owners with contaminated wells, among other requirements. All materials relative to status of consent order requirements must be published to a public website, https://www.chemours.com/en/about-chemours/global-reach/fayetteville-works/compliance-testing . One requirement under

605-667: A factor of ten. Over half of agricultural chemicals contain C-F bonds. A common example is trifluralin . The effectiveness of organofluorine compounds is attributed to their metabolically stability, i.e. they are not degraded rapidly so remain active. Also, fluorine acts as a bioisostere of the hydrogen atom. Fluorocarbons are also used as a propellant for metered-dose inhalers used to administer some asthma medications. The current generation of propellant consists of hydrofluoroalkanes (HFA), which have replaced CFC -propellant-based inhalers. CFC inhalers were banned as of 2008 as part of

726-536: A few hundred feet tall. It is divided by a low water divide running north and south. The larger portion of the state is on the west of this and gradually slopes toward Lake Michigan. The highest point in the Lower Peninsula is either Briar Hill at 1,705 feet (520 m), or one of several points nearby in the vicinity of Cadillac . The lowest point is the surface of Lake Erie at 571 feet (174 m). The geographic orientation of Michigan's peninsulas makes for

847-660: A landmark during the day to safely guide the passenger ships and freighters traveling the Great Lakes (see: lighthouses in the United States ). The state's rivers are generally small, short and shallow, and few are navigable. The principal ones include the Detroit River, St. Marys River, and St. Clair River which connect the Great Lakes; the Au Sable , Cheboygan , and Saginaw , which flow into Lake Huron;

968-563: A long distance between the ends of the state. Ironwood , in the far western Upper Peninsula, lies 630 miles (1,010 kilometers) by highway from Lambertville in the Lower Peninsula's southeastern corner. The geographic isolation of the Upper Peninsula from Michigan's political and population centers makes the region culturally and economically distinct. Frequent attempts to establish the Upper Peninsula as its own state have failed to gain traction. A feature of Michigan that gives it

1089-931: A long-term risk for neurodegenerative disorders, particularly Parkinson's disease, due to its impact on key neuronal processes. Recent research has also underscored the potential for GenX to disrupt glucose and lipid metabolism during critical developmental periods. A 2021 study published in Environment International investigated the effects of prenatal exposure to GenX in Sprague-Dawley rats, revealing significant maternal and neonatal adverse outcomes, such as increased maternal liver weight, altered lipid profiles, and reduced glycogen accumulation in neonatal livers, resulting in hypoglycemia. Additionally, neonatal mortality and lower birth weights were observed at higher doses of GenX . A 2024 study in Science of

1210-625: A nearly bloodless siege in 1812. A U.S. attempt to retake Detroit resulted in a severe American defeat in the River Raisin Massacre . This battle, still ranked as the bloodiest ever fought in the state, had the highest number of American casualties of any battle of the war. Michigan was recaptured by the Americans in 1813 after the Battle of Lake Erie . They used Michigan as a base to launch an invasion of Canada, which culminated in

1331-430: A permanent community there would strengthen French control over the upper Great Lakes and discourage British aspirations. The hundred soldiers and workers who accompanied Cadillac built a fort enclosing one arpent (about 0.85 acres (3,400 m ), the equivalent of just under 200 feet (61 m) per side) and named it Fort Pontchartrain . Cadillac's wife, Marie Thérèse Guyon, soon moved to Detroit, becoming one of

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1452-406: A prochiral substrate, rely on electrophilic fluorination reagents. Illustrative of this approach is the preparation of a precursor to anti-inflammatory agents: A specialized but important method of electrophilic fluorination involves electrosynthesis . The method is mainly used to perfluorinate, i.e. replace all C–H bonds by C–F bonds. The hydrocarbon is dissolved or suspended in liquid HF, and

1573-782: A replacement for long-chain PFAS chemicals, can lead to complex health effects. GenX has been linked to alterations in immune responses and metabolic processes, as observed in both human and animal studies. For instance, in a study using Monodelphis domestica , GenX exposure upregulated genes associated with inflammation and fatty acid transport. Another study on mice showed that GenX suppressed innate immune responses to inhaled carbon black nanoparticles, while simultaneously promoting lung cell proliferation, including macrophages and epithelial cells. These findings suggest that GenX may have immunosuppressive effects, potentially increasing susceptibility to respiratory agents while encouraging cellular growth in

1694-596: A significant amount of population due to global competition and the dramatic unavailability of manufacturing jobs. Meanwhile, Michigan had increased use of technology, specifically when the IBM Personal Computer started selling in the state, in which became mostly used at work. Michigan became the leading auto-producing state in the U.S., with the industry primarily located throughout the Midwestern United States ; Ontario, Canada; and

1815-423: A surge of interest in fluorinated pharmaceuticals and agrichemicals. The discovery of the noble gas compounds , e.g. XeF 4 , provided a host of new reagents starting in the early 1960s. In the 1970s, fluorodeoxyglucose was established as a useful reagent in F positron emission tomography . In Nobel Prize-winning work, CFC's were shown to contribute to the depletion of atmospheric ozone. This discovery alerted

1936-408: A variety of adverse health effects. While it was originally marketed as a safer alternative to legacy PFAS, research suggests that GenX poses significant health risks similar to those associated with its predecessor. Studies have demonstrated that the liver is especially vulnerable to GenX exposure. Animal research has shown that even low doses of GenX can cause liver enlargement and damage. Similarly,

2057-810: A variety of oxygen-containing groups into fluorides. The usual reagent is sulfur tetrafluoride : A more convenient alternative to SF 4 is the diethylaminosulfur trifluoride , which is a liquid whereas SF 4 is a corrosive gas: Apart from DAST, a wide variety of similar reagents exist, including, but not limited to, 2-pyridinesulfonyl fluoride (PyFluor) and N -tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor). Many of these display improved properties such as better safety profile, higher thermodynamic stability, ease of handling, high enantioselectivity, and selectivity over elimination side-reactions. Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF 3 Si(CH 3 ) 3 ,

2178-427: A warmer climate ( Köppen climate classification Dfa ) with hot summers and cold winters. The northern part of the Lower Peninsula and the entire Upper Peninsula has a more severe climate (Köppen Dfb ), with warm, but shorter summers and longer, cold to very cold winters. Some parts of the state average high temperatures below freezing from December through February, and into early March in the far northern parts. During

2299-571: A young research chemist who worked at DuPont 's Jackson Laboratory in Deepwater, New Jersey , accidentally discovered polytetrafluoroethylene (PTFE). Subsequent major developments, especially in the US, benefited from expertise gained in the production of uranium hexafluoride. Starting in the late 1940s, a series of electrophilic fluorinating methodologies were introduced, beginning with CoF 3 . Electrochemical fluorination (" electrofluorination ")

2420-425: Is fluoroacetate , a toxin found in a few species of plants. Others include fluorooleic acid, fluoroacetone , nucleocidin (4'-fluoro-5'-O-sulfamoyladenosine), fluorothreonine , and 2-fluorocitrate . Several of these species are probably biosynthesized from fluoroacetaldehyde . The enzyme fluorinase catalyzed the synthesis of 5'-deoxy-5'-fluoroadenosine (see scheme to right). Organofluorine chemistry began in

2541-493: Is fluoroacetate , which occurs as a plant defence against herbivores in at least 40 plants in Australia, Brazil and Africa. Other biologically synthesized organofluorines include ω-fluoro fatty acids , fluoroacetone , and 2-fluorocitrate which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde. Adenosyl-fluoride synthase is an enzyme capable of biologically synthesizing

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2662-846: Is a state in the Great Lakes region of the Upper Midwest region of the United States . It borders Wisconsin to the southwest in the Upper Peninsula , and Indiana and Ohio to the south in the Lower Peninsula ; it is also connected by Lakes Superior , Michigan , Huron , and Erie to Minnesota and Illinois , and the Canadian province of Ontario . With a population of nearly 10.12 million and an area of 96,716 sq mi (250,490 km ), Michigan

2783-430: Is a solid acid that is used as the membrane in most low temperature fuel cells . The bifunctional monomer 4,4'-difluorobenzophenone is a precursor to PEEK -class polymers. In contrast to the many naturally-occurring organic compounds containing the heavier halides , chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known. The most common natural organofluorine species

2904-686: Is a solid. Hydrofluorocarbons (HFCs), organic compounds that contain fluorine and hydrogen atoms, are the most common type of organofluorine compounds. They are commonly used in air conditioning and as refrigerants in place of the older chlorofluorocarbons such as R-12 and hydrochlorofluorocarbons such as R-21 . They do not harm the ozone layer as much as the compounds they replace; however, they do contribute to global warming . Their atmospheric concentrations and contribution to anthropogenic greenhouse gas emissions are rapidly increasing, causing international concern about their radiative forcing . Fluorocarbons with few C-F bonds behave similarly to

3025-750: Is a strong acid, it deprotonates into its conjugate base, which can then be detected in the water. In North Carolina , the Chemours Fayetteville plant released GenX compounds into the Cape Fear River , which is a drinking water source for the Wilmington area. A documentary film, The Devil We Know ; a fictional dramatization, Dark Waters ; and a nonfiction memoir, Exposure: Poisoned Water, Corporate Greed, and One Lawyer's Twenty-Year Battle Against DuPont by Robert Bilott , subsequently publicized

3146-453: Is an oxidation-resistant polar solvent. The development of organofluorine chemistry has contributed many reagents of value beyond organofluorine chemistry. Triflic acid (CF 3 SO 3 H) and trifluoroacetic acid (CF 3 CO 2 H) are useful throughout organic synthesis . Their strong acidity is attributed to the electronegativity of the trifluoromethyl group that stabilizes the negative charge. The triflate-group (the conjugate base of

3267-641: Is bounded on the south by the states of Ohio and Indiana , sharing land and water boundaries with both. Michigan's western boundaries are almost entirely water boundaries, from south to north, with Illinois and Wisconsin in Lake Michigan; then a land boundary with Wisconsin and the Upper Peninsula, that is principally demarcated by the Menominee and Montreal Rivers ; then water boundaries again, in Lake Superior, with Wisconsin and Minnesota to

3388-407: Is converted into its ammonium salt that is the official GenX compound. The chemical process uses 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid (FRD-903) to generate ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate (FRD-902) and heptafluoropropyl 1,2,2,2-tetrafluoroethyl ether (E1). When GenX contacts water, it releases the ammonium group to become HFPO-DA. Because HFPO-DA

3509-489: Is home to the country's three major automobile companies (whose headquarters are all in Metro Detroit). Once exploited for logging and mining, today the sparsely populated Upper Peninsula is important for tourism because of its abundance of natural resources. The Lower Peninsula is a center of manufacturing , forestry , agriculture , services , and high-tech industry. When the first European explorers arrived,

3630-526: Is rugged. The state's highest point, in the Huron Mountains northwest of Marquette, is Mount Arvon at 1,979 feet (603 m). The peninsula is as large as Connecticut, Delaware, Massachusetts, and Rhode Island combined but has fewer than 330,000 inhabitants. The people are sometimes called "Yoopers" (from "U.P.'ers"), and their speech (the " Yooper dialect ") has been heavily influenced by the numerous Scandinavian and Canadian immigrants who settled

3751-562: Is the 10th-largest state by population, the 11th-largest by area, and the largest by area east of the Mississippi River . Its capital is Lansing , and its largest city is Detroit . Metro Detroit is among the nation's most populous and largest metropolitan economies. The name derives from a gallicized variant of the original Ojibwe word ᒥᓯᑲᒥ ( mishigami ), meaning "large water" or "large lake". Michigan consists of two peninsulas . The Lower Peninsula resembles

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3872-402: Is the gas tetrafluoromethane (CF 4 ). Liquids include perfluorooctane and perfluorodecalin. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. Fluorocarbons are more chemically and thermally stable than hydrocarbons, reflecting the relative inertness of the C-F bond. They are also relatively lipophobic . Because of

3993-436: Is the most common source of fluoride in the synthesis of organofluorine compounds. Such reactions are often catalysed by metal fluorides such as chromium trifluoride. 1,1,1,2-Tetrafluoroethane , a replacement for CFC's, is prepared industrially using this approach: Notice that this transformation entails two reaction types, metathesis (replacement of Cl by F ) and hydrofluorination of an alkene . Deoxofluorination convert

4114-521: Is the state's largest metropolitan area (roughly 50% of the population resides there) and the eleventh largest in the United States. The Grand Rapids metropolitan area in Western Michigan is the state's fastest-growing metro area, with more than 1.3 million residents as of 2006 . Michigan consists of two peninsulas separated by the Straits of Mackinac . The 45th parallel north runs through

4235-471: Is used as a source of the trifluoromethyl group, for example. Among the available fluorinated building blocks are CF 3 X (X = Br, I), C 6 F 5 Br, and C 3 F 7 I. These species form Grignard reagents that then can be treated with a variety of electrophiles . The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails". A special but significant application of

4356-560: The American Revolution . When Quebec split into Lower and Upper Canada in 1791, Michigan was part of Kent County , Upper Canada. It held its first democratic elections in August 1792 to send delegates to the new provincial parliament at Newark (now Niagara-on-the-Lake ). Under terms negotiated in the 1794 Jay Treaty , Britain withdrew from Detroit and Michilimackinac in 1796. It retained control of territory east and south of

4477-710: The Battle of the Thames . But the more northern areas of Michigan were held by the British until the peace treaty restored the old boundaries. A number of forts, including Fort Wayne , were built by the United States in Michigan during the 19th century out of fears of renewed fighting with Britain. Michigan Territory governor and judges established the University of Michigan in 1817, as the Catholepistemiad, or

4598-531: The Brunswick County Government filed a federal lawsuit alleging that DuPont failed to disclose research regarding potential risks from the chemical. In spring 2018, Cape Fear River Watch sued Chemours for Clean Water Act violations and sued the NCDEQ for inaction. After Cape Fear River Watch's suits were filed, NCDEQ filed a suit against Chemours, the result of all 3 lawsuits culminated in

4719-551: The Guardian Building , each of which has been designated as a National Historic Landmark (NHL). In 1927 a school bombing took place in Clinton County . The Bath School disaster resulted in the deaths of 38 schoolchildren and constitutes the deadliest mass murder in a school in U.S. history. Michigan converted much of its manufacturing to satisfy defense needs during World War II ; it manufactured 10.9% of

4840-653: The Montreal Protocol because of environmental concerns with the ozone layer. HFA propellant inhalers like FloVent and ProAir ( Salbutamol ) have no generic versions available as of October 2014. Fluorosurfactants, which have a polyfluorinated "tail" and a hydrophilic "head", serve as surfactants because they concentrate at the liquid-air interface due to their lipophobicity . Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactants perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two of

4961-708: The Montreal Protocol . As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example is difluorocarbene , CF 2 , which is a singlet whereas carbene (CH 2 ) has a triplet ground state. This difference is significant because difluorocarbene is a precursor to tetrafluoroethylene . Perfluorinated compounds are fluorocarbon derivatives, as they are closely structurally related to fluorocarbons. However, they also possess new atoms such as nitrogen , iodine , or ionic groups, such as perfluorinated carboxylic acids . Organofluorine compounds are prepared by numerous routes, depending on

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5082-587: The Netherlands were especially numerous. Migration from Appalachia and of Black Southerners as part of the Great Migration increased in the 1930s, with many settling in Metro Detroit. Although Michigan has developed a diverse economy, in the early 20th century it became widely known as the center of the U.S. automotive industry , which developed as a major national economic force. It

5203-560: The North Country National Scenic Trail passes through Michigan. With 78 state parks , 19 state recreation areas, and six state forests , Michigan has the largest state park and state forest system of any state. Michigan has a continental climate with two distinct regions. The southern and central parts of the Lower Peninsula (south of Saginaw Bay and from the Grand Rapids area southward) have

5324-581: The Ontonagon , and Tahquamenon , which flow into Lake Superior; and the St. Joseph , Kalamazoo , Grand , Muskegon , Manistee , and Escanaba , which flow into Lake Michigan. The state has 11,037 inland lakes—totaling 1,305 square miles (3,380 km ) of inland water—in addition to 38,575 square miles (99,910 km ) of Great Lakes waters. No point in Michigan is more than six miles (9.7 km) from an inland lake or more than 85 miles (137 km) from one of

5445-675: The Paris Agreement , hydrofluorocarbons have other international negotiations. In September 2016, the so-called New York Declaration urged a global reduction in the use of HFCs. On 15 October 2016, due to these chemicals contribution to climate change , negotiators from 197 nations meeting at the summit of the United Nations Environment Programme in Kigali, Rwanda reached a legally-binding accord to phase out hydrofluorocarbons (HFCs) in an amendment to

5566-596: The U.S. Environmental Protection Agency (EPA) published drinking water health advisories , which are non-regulatory technical documents, for GenX and PFBS . The lifetime health advisories and health effects support documents assist federal, state, tribal, and local officials and managers of drinking water systems in protecting public health when these chemicals are present in drinking water. EPA has listed recommended steps that consumers may take to reduce possible exposure to GenX and other PFAS chemicals. Organofluorine compound Organofluorine chemistry describes

5687-487: The automotive industry . Ford's development of the moving assembly line in Highland Park marked a new era in transportation. Like the steamship and railroad, mass production of automobiles was a far-reaching development. More than the forms of public transportation, the affordable automobile transformed private life. Automobile production became the major industry of Detroit and Michigan, and permanently altered

5808-540: The chemistry of organofluorine compounds , organic compounds that contain a carbon–fluorine bond . Organofluorine compounds find diverse applications ranging from oil and water repellents to pharmaceuticals , refrigerants, and reagents in catalysis . In addition to these applications, some organofluorine compounds are pollutants because of their contributions to ozone depletion , global warming , bioaccumulation , and toxicity . The area of organofluorine chemistry often requires special techniques associated with

5929-436: The homolytic cleavage of the carbon-chlorine bonds; their use is largely prohibited by the Montreal Protocol . Hydrofluorocarbons (HFCs), such as tetrafluoroethane , serve as CFC replacements because they do not catalyze ozone depletion. Oxygen exhibits a high solubility in perfluorocarbon compounds, reflecting on their lipophilicity. Perfluorodecalin has been demonstrated as a blood substitute transporting oxygen to

6050-478: The 1800s with the development of organic chemistry. The first organofluorine compound was discovered in 1835, when Dumas and Péligot distilled dimethyl sulfate with potassium fluoride and got fluoromethane . In 1862, Alexander Borodin pioneered a now-common method of halogen exchange: he acted on benzoyl chloride with potassium bifluoride and first synthesized benzoyl fluoride . Besides salts, organofluorine compounds were often prepared using HF as

6171-437: The 1830s, Michigan had 30,000 residents, more than enough to apply and qualify for statehood. On November 1, 1935, the U.S. Post Office issued a commemorative 3-cent stamp celebrating the 100th anniversary of Michigan statehood. Michigan's statehood, however, wasn't officially established until January 26, 1837, but since the campaign for statehood actually began in 1835, Michigan chose to hold its centennial celebration in 1935,

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6292-851: The British forces, ending the French and Indian War (1754–1763), the North American front of the Seven Years' War in Europe. Under the 1763 Treaty of Paris , Michigan and the rest of New France east of the Mississippi River were ceded by defeated France to Great Britain. After the Quebec Act was passed in 1774, Michigan became part of the British Province of Quebec . By 1778, Detroit's population reached 2,144 and it

6413-521: The Detroit River, which are now included in Ontario, Canada. Questions remained over the boundary for many years, and the United States did not have uncontested control of the Upper Peninsula and Drummond Island until 1818 and 1847, respectively. During the War of 1812 , the United States forces at Fort Detroit surrendered Michigan Territory (effectively consisting of Detroit and the surrounding area) after

6534-629: The F source because elemental fluorine, as its discoverer Henri Moissan and his followers found out, was prone to explosions when mixed with organics. Frédéric Swarts also introduced antimony fluoride in this role in 1898. The nonflammability and nontoxicity of the chlorofluorocarbons CCl 3 F and CCl 2 F 2 attracted industrial attention in the 1920s. General Motors settled on these CFCs as refrigerants and had DuPont produce them via Swarts' method. In 1931, Bancroft and Wherty managed to solve fluorine's explosion problem by diluting it with inert nitrogen. On April 6, 1938, Roy J. Plunkett

6655-685: The French established a trading post and Fort St. Joseph along the St. Joseph River at the present-day city of Niles . In 1701, French explorer and army officer Antoine de la Mothe Cadillac founded Fort Pontchartrain du Détroit or "Fort Pontchartrain on-the-Strait" on the strait, known as the Detroit River , between lakes Saint Clair and Erie . Cadillac had convinced King Louis XIV's chief minister, Louis Phélypeaux, Comte de Pontchartrain , that

6776-631: The Great Lakes. The state is home to several areas maintained by the National Park Service including: Isle Royale National Park , in Lake Superior, about 30 miles (48 km) southeast of Thunder Bay, Ontario. Other national protected areas in the state include: Keweenaw National Historical Park , Pictured Rocks National Lakeshore , Sleeping Bear Dunes National Lakeshore , Huron National Forest , Manistee National Forest , Hiawatha National Forest , Ottawa National Forest and Father Marquette National Memorial . The largest section of

6897-504: The Lower Peninsula, Michigan is drained by the Great Lakes- St. Lawrence watershed and is the only state with the majority of its land thus drained. No point in the state is more than six miles (9.7 km) from a natural water source or more than 85 miles (137 km) from a Great Lakes shoreline. The Great Lakes that border Michigan from east to west are Lake Erie , Lake Huron , Lake Michigan and Lake Superior . The state

7018-548: The Southern United States. With almost ten million residents in 2010, Michigan is a large and influential state, ranking tenth in population among the fifty states. Detroit is the centrally located metropolitan area of the Great Lakes megalopolis and the second-largest metropolitan area in the U.S. (after Chicago ) linking the Great Lakes system. The Metro Detroit area in Southeast Michigan

7139-949: The Total Environment expanded upon these findings in mice, demonstrating that gestational exposure to GenX led to increased liver weight, elevated liver enzyme levels (e.g., ALT and AST), and decreased glycogen storage capacity in the liver. Disruptions in gut flora and the intestinal mucosal barrier were also noted, further linking GenX exposure to hepatotoxicity. Both studies revealed significant alterations in gene expression, particularly in pathways regulating glucose and lipid metabolism. Genes such as CYP4A14, Sult2a1, and Igfbp1 were upregulated, which may have long-term implications for metabolic health. These findings suggest that gestational GenX exposure could trigger metabolic disorders and liver toxicity, posing potential health risks for populations exposed to GenX through contaminated water sources . Studies have demonstrated that exposure to GenX,

7260-639: The U.S.), an Anishinaabe tribe, were established in Michigan's Upper Peninsula and northern and central Michigan . Bands also inhabited Ontario and southern Manitoba , Canada; and northern Wisconsin , and northern and north-central Minnesota . The Ottawa Indians lived primarily south of the Straits of Mackinac in northern, western , and southern Michigan , but also in southern Ontario, northern Ohio, and eastern Wisconsin. The Potawatomi were in southern and western Michigan, in addition to northern and central Indiana, northern Illinois, southern Wisconsin, and southern Ontario. Other Algonquian tribes in Michigan, in

7381-513: The United States military armaments produced during the war, ranking second (behind New York ) among the 48 states. Detroit continued to expand through the 1950s, at one point doubling its population in a decade. After World War II, housing was developed in suburban areas outside city cores to meet demand for residences. The federal government subsidized the construction of interstate highways , which were intended to strengthen military access, but also allowed commuters and business traffic to travel

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7502-697: The University of Michigania. The population grew slowly until the opening in 1825 of the Erie Canal through the Mohawk Valley in New York, connecting the Great Lakes to the Hudson River and New York City. The new route attracted a large influx of settlers to the Michigan territory. They worked as farmers, lumbermen, shipbuilders, and merchants and shipped out grain, lumber, and iron ore. By

7623-633: The Wilmington-area drinking water sourced from the Cape Fear river. In September 2017, the North Carolina Department of Environmental Quality (NCDEQ) ordered Chemours to halt discharges of all fluorinated compounds into the river. Following a chemical spill one month later, NCDEQ cited Chemours for violating provisions in its National Pollutant Discharge Elimination System wastewater discharge permit. In November 2017,

7744-463: The area during the lumbering and mining boom of the late 19th century. The Lower Peninsula is shaped like a mitten and many residents hold up a hand to depict where they are from. It is 277 miles (446 km) long from north to south and 195 miles (314 km) from east to west and occupies nearly two-thirds of the state's land area. The surface of the peninsula is generally level, broken by conical hills and glacial moraines usually not more than

7865-560: The area, settling largely along the waterways. After France's defeat in the French and Indian War in 1762, the region came under British rule. Britain ceded the territory to the newly independent United States after its defeat in the American Revolutionary War . The area was part of the larger Northwest Territory until 1800, when western Michigan became part of the Indiana Territory . Michigan Territory

7986-516: The blood of Cape Fear area residents. In 2020 Michigan adopted drinking water standards for 5 previously unregulated PFAS compounds including HFPO-DA which has a maximum contaminant level (MCL) of 370 parts per trillion (ppt). Two previously regulated PFAS compounds PFOA and PFOS had their acceptable limits lowered to 8 ppt and 16 ppt respectively. In 2022 Virginia's Roanoke River had become contaminated by GenX at levels reported to be 1.3 million parts per trillion. GenX has been shown to cause

8107-457: The carbon–fluorine bond. Organofluorine chemistry impacts many areas of everyday life and technology. The C-F bond is found in pharmaceuticals , agrichemicals , fluoropolymers , refrigerants , surfactants , anesthetics , oil-repellents , catalysis , and water-repellents , among others. The carbon-fluorine bond is commonly found in pharmaceuticals and agrochemicals. An estimated 1/5 of pharmaceuticals contain fluorine, including several of

8228-475: The coast is much indented. Keweenaw Bay, Whitefish Bay , and the Big and Little Bays De Noc are the principal indentations on the Upper Peninsula. The Grand and Little Traverse , Thunder , and Saginaw bays indent the Lower Peninsula. Michigan has the second longest shoreline of any state—3,288 miles (5,292 km), including 1,056 miles (1,699 km) of island shoreline. The state has numerous large islands ,

8349-559: The coldest recorded temperature is −51 °F (−46 °C) at Vanderbilt on February 9, 1934. The state averages 30 days of thunderstorm activity per year. These can be severe, especially in the southern part of the state. The state averages 17 tornadoes per year, which are more common in the state's extreme southern section. Portions of the southern border have been almost as vulnerable historically as states further west and in Tornado Alley . For this reason, many communities in

8470-424: The concept of like-dissolves-like in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents. Because of the relative inertness of the C-F bond, such fluorous phases are compatible with harsh reagents. This theme has spawned techniques of "fluorous tagging and fluorous protection . Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions,

8591-759: The degree and regiochemistry of fluorination sought and the nature of the precursors. The direct fluorination of hydrocarbons with F 2 , often diluted with N 2 , is useful for highly fluorinated compounds: Such reactions however are often unselective and require care because hydrocarbons can uncontrollably "burn" in F 2 , analogous to the combustion of hydrocarbon in O 2 . For this reason, alternative fluorination methodologies have been developed. Generally, such methods are classified into two classes. Electrophilic fluorination rely on sources of "F ". Often such reagents feature N-F bonds, for example F-TEDA-BF 4 . Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from

8712-427: The development of new methods for forming C–F bonds. Because of the short half-life of F, these syntheses must be highly efficient, rapid, and easy. Illustrative of the methods is the preparation of fluoride-modified glucose by displacement of a triflate by a labeled fluoride nucleophile: Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals. The most common example

8833-531: The discharges, leading to controversy over possible health effects. HFPO-DA was first reported to be in the Cape Fear River in 2012 and an additional eleven polyfluoroalkyl substances (PFAS) were reported 2014. These results were published as a formal paper in 2015. The following year, North Carolina State University and the EPA jointly published a study demonstrating HFPO-DA and other PFAS were present in

8954-671: The distinct shape of a mitten is the Thumb , which projects into Lake Huron, forming Saginaw Bay . Other notable peninsulas of Michigan include the Keweenaw Peninsula , which projects northeasterly into Lake Superior from the Upper Peninsula and largely comprising Michigan's Copper Country region, and the Leelanau Peninsula , projecting from the Lower Peninsula into Lake Michigan, forming Michigan's "little finger". Numerous lakes and marshes mark both peninsulas, and

9075-691: The entire Lower Peninsula. The Upper Peninsula exhibits Lower Silurian sandstones, limestones, copper and iron bearing rocks, corresponding to the Huronian system of Canada . The central portion of the Lower Peninsula contains coal measures and rocks of the Pennsylvanian period. Devonian and sub-Carboniferous deposits are scattered over the entire state. Michigan rarely experiences earthquakes , and those that it does experience are generally smaller ones that do not cause significant damage. A 4.6-magnitude earthquake struck in August 1947. More recently,

9196-439: The first European women to settle in what was considered the wilderness of Michigan. The town quickly became a major fur-trading and shipping post. The Église de Saint-Anne (Catholic Church of Saint Anne) was founded the same year. While the original building does not survive, the congregation remains active. Cadillac later departed to serve as the French governor of Louisiana from 1710 to 1716. French attempts to consolidate

9317-535: The five Great Lakes and Lake St. Clair . It also has 64,980 inland lakes and ponds . Michigan has the second-most water area of any state, behind only Alaska. The area was first occupied by a succession of Native American tribes over thousands of years. In the 17th century, French explorers claimed it as part of the New France colony, when it was largely inhabited by Indigenous peoples. French and Canadian traders and settlers, Métis , and others migrated to

9438-547: The fluorinated building block approach is the synthesis of tetrafluoroethylene , which is produced on a large-scale industrially via the intermediacy of difluorocarbene. The process begins with the thermal (600-800 °C) dehydrochlorination of chlorodifluoromethane : Sodium fluorodichloroacetate (CAS# 2837-90-3) is used to generate chlorofluorocarbene, for cyclopropanations. The usefulness of fluorine-containing radiopharmaceuticals in F- positron emission tomography has motivated

9559-565: The fur trade led to the Fox Wars , in which the Meskwaki (Fox) and their allies fought the French and their Native allies. At the same time, the French strengthened Fort Michilimackinac at the Straits of Mackinac to better control their lucrative fur-trading empire. By the mid-18th century, the French also occupied forts at present-day Niles and Sault Ste. Marie, though most of the rest of

9680-731: The handling of fluorinating agents. Fluorine has several distinctive differences from all other substituents encountered in organic molecules. As a result, the physical and chemical properties of organofluorines can be distinctive in comparison to other organohalogens . In comparison to aryl chlorides and bromides, aryl fluorides form Grignard reagents only reluctantly. On the other hand, aryl fluorides, e.g. fluoro anilines and fluoro phenols , often undergo nucleophilic substitution efficiently. Formally, fluorocarbons only contain carbon and fluorine. Sometimes they are called perfluorocarbons. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon

9801-423: The kidneys are also sensitive to GenX, with chronic exposure leading to renal toxicity. These effects highlight the potential dangers of prolonged exposure to even small amounts of the chemical. There is increasing concern about the carcinogenic potential of GenX. Research in animal models has linked exposure to various cancers, including liver, pancreatic, and testicular cancers. Although data on humans are limited,

9922-708: The late 19th to early 20th century, working in lumbering areas in counties on the Lake Huron side of the Lower Peninsula, such as the Saginaw Valley, Alpena, and Cheboygan counties, as well as throughout the Upper Peninsula, with large concentrations in Escanaba and the Keweenaw Peninsula . The first statewide meeting of the Republican Party took place on July 6, 1854, in Jackson, Michigan , where

10043-458: The lungs, raising concerns about respiratory health risks. This research highlights the potential health implications of GenX exposure, particularly its impact on immune system function and cell proliferation, which may contribute to both immune suppression and adverse health outcomes like inflammation or respiratory diseases. These findings raise concerns about the long-term impact on human health, especially in vulnerable populations. In June 2022

10164-512: The lungs. Fluorine-substituted ethers are volatile anesthetics , including the commercial products methoxyflurane , enflurane , isoflurane , sevoflurane and desflurane . Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane . Perfluorinated alkanes are used as blood substitutes . The solvent 1,1,1,2-tetrafluoroethane has been used for extraction of natural products such as taxol , evening primrose oil , and vanillin . 2,2,2-trifluoroethanol

10285-592: The mixture is electrolyzed at 5–6 V using Ni anodes . The method was first demonstrated with the preparation of perfluoropyridine ( C 5 F 5 N ) from pyridine ( C 5 H 5 N ). Several variations of this technique have been described, including the use of molten potassium bifluoride or organic solvents . The major alternative to electrophilic fluorination is nucleophilic fluorination using reagents that are sources of "F ," for Nucleophilic displacement typically of chloride and bromide. Metathesis reactions employing alkali metal fluorides are

10406-673: The most populous tribes were the Algonquian peoples , which include the Anishinaabe groups of Ojibwe , Odaawaa/Odawa (Ottawa) , and the Boodewaadamii/Bodéwadmi (Potawatomi) . The three nations coexisted peacefully as part of a loose confederation called the Council of Three Fires . The Ojibwe, whose numbers are estimated to have been at least 35,000, were the largest. The Ojibwe Indians (also known as Chippewa in

10527-579: The most studied because of their ubiquity, proposed toxicity, and long residence times in humans and wildlife. Triphenylphosphine has been modified by attachment of perfluoroalkyl substituents that confer solubility in perfluorohexane as well as supercritical carbon dioxide . As a specific example, [(C 8 F 17 C 3 H 6 -4-C 6 H 4 ) 3 P. Fluorinated compounds often display distinct solubility properties. Dichlorodifluoromethane and chlorodifluoromethane were at one time widely used refrigerants. CFCs have potent ozone depletion potential due to

10648-456: The nation. Many private colleges were founded as well, and the smaller cities established high schools late in the century. Michigan's economy underwent a transformation at the turn of the 20th century. Many individuals, including Ransom E. Olds , John and Horace Dodge , Henry Leland , David Dunbar Buick , Henry Joy , Charles King , and Henry Ford , provided the concentration of engineering know-how and technological enthusiasm to develop

10769-574: The order was for non-targeted analysis which found 257 "unknown" PFAS being released from Fayetteville Works, (aside from the 100 'known' PFAS which can be quantified. Cape Fear River Watch published that their research of the NC DEQ permit file indicates that the first PFAS byproducts were likely released from Fayetteville Works in 1976 with the production of Nafion which uses HFPO in production (otherwise known as GenX) and creates byproducts termed Nafion Byproducts 1 through 5, some of which have been found in

10890-438: The parent hydrocarbons, but their reactivity can be altered significantly. For example, both uracil and 5-fluorouracil are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug. The use of the C-F bond in pharmaceuticals is predicated on this altered reactivity. Several drugs and agrochemicals contain only one fluorine center or one trifluoromethyl group. Unlike other greenhouse gases in

11011-682: The party adopted its platform. The state was predominantly Republican until the 1930s, reflecting the political continuity of migrants from across the Northern Tier of New England and New York. Michigan made a significant contribution to the Union in the American Civil War and sent more than forty regiments of volunteers to the federal armies. Michigan modernized and expanded its system of education in this period. The Michigan State Normal School, now Eastern Michigan University ,

11132-441: The population boom. By the 1930s, so many immigrants had arrived that more than 30 languages were spoken in the public schools, and ethnic communities celebrated in annual heritage festivals. Over the years immigrants and migrants contributed greatly to Detroit's diverse urban culture, including popular music trends. The influential Motown Sound of the 1960s was led by a variety of individual singers and groups. Grand Rapids ,

11253-546: The principal ones being the North Manitou and South Manitou , Beaver , and Fox groups in Lake Michigan; Isle Royale and Grande Isle in Lake Superior; Marquette, Bois Blanc , and Mackinac islands in Lake Huron; and Neebish , Sugar , and Drummond islands in St. Mary's River . Michigan has about 150 lighthouses , the most of any U.S. state. The first lighthouses in Michigan were built between 1818 and 1822. They were built to project light at night and to serve as

11374-491: The products being easily separated from the spent tin reagent by extraction using fluorinated solvents. Hydrophobic fluorinated ionic liquids , such as organic salts of bistriflimide or hexafluorophosphate , can form phases that are insoluble in both water and organic solvents, producing multiphasic liquids . Fluorine-containing compounds are often featured in noncoordinating or weakly coordinating anions. Both tetrakis(pentafluorophenyl)borate, B(C 6 F 5 ) 4 , and

11495-412: The reduced intermolecular van der Waals interactions , fluorocarbon-based compounds are sometimes used as lubricants or are highly volatile. Fluorocarbon liquids have medical applications as oxygen carriers. The structure of organofluorine compounds can be distinctive. As shown below, perfluorinated aliphatic compounds tend to segregate from hydrocarbons. This "like dissolves like effect" is related to

11616-587: The region more easily. Since 1960, modern advances in the auto industry have led to increased automation, high-tech industry, and increased suburban growth. Longstanding tensions in Detroit culminated in the Twelfth Street riot in July 1967. During the late 1970s and the early 1980s, increasing fuel costs and other factors made significantly more global competition and recession among families. Michigan lost

11737-517: The region remained unsettled by Europeans. France offered free land to attract families to Detroit, which grew to 800 people in 1765. It was the largest city between Montreal and New Orleans. French settlers also established small farms south of the Detroit River opposite the fort, near a Jesuit mission and Huron village. From 1660 until the end of French rule, Michigan was part of the Royal Province of New France . In 1760, Montreal fell to

11858-991: The related tetrakis[3,5-bis(trifluoromethyl)phenyl]borate , are useful in Ziegler-Natta catalysis and related alkene polymerization methodologies. The fluorinated substituents render the anions weakly basic and enhance the solubility in weakly basic solvents, which are compatible with strong Lewis acids. Organofluorine compounds enjoy many niche applications in materials science . With a low coefficient of friction , fluid fluoropolymers are used as specialty lubricants. Fluorocarbon-based greases are used in demanding applications. Representative products include Fomblin and Krytox , made by Solvay Solexis and DuPont , respectively. Certain firearm lubricants such as "Tetra Gun" contain fluorocarbons. Capitalizing on their nonflammability, fluorocarbons are used in fire fighting foam. Organofluorine compounds are components of liquid crystal displays . The polymeric analogue of triflic acid, nafion

11979-444: The repressive marker H3K27me3, which is associated with neurodegeneration. These changes were accompanied by disruptions in mitochondrial function and an increase in intracellular calcium levels, which are critical markers of neuronal health. Notably, GenX exposure led to altered expression of α-synuclein, a protein closely linked to the development of Parkinson's disease. The findings suggest that developmental exposure to GenX may pose

12100-528: The results from these studies have prompted further investigation into the possible cancer risks posed by GenX. Two 2023 studies have identified potential neurotoxic effects of GenX, particularly during critical developmental windows. Pre-differentiation exposure of human dopaminergic-like neurons (SH-SY5Y cells) to low-dose GenX (0.4 and 4 μg/L) resulted in persistent alterations in neuronal characteristics. The study reported significant changes in nuclear morphology, chromatin arrangement, and increased expression of

12221-528: The second-largest city in Michigan also became an important center of manufacturing. Since 1838, the city has been noted for its furniture industry. In the 21st century, it is home to five of the world's leading office furniture companies. Grand Rapids is home to a number of major companies including Steelcase , Amway , and Meijer . Grand Rapids is also an important center for GE Aviation Systems . Michigan held its first United States presidential primary election in 1910. With its rapid growth in industry, it

12342-435: The shape of a mitten , and comprises a majority of the state's land area. The Upper Peninsula (often called "the U.P.") is separated from the Lower Peninsula by the Straits of Mackinac , a five-mile (8 km) channel that joins Lake Huron to Lake Michigan. The Mackinac Bridge connects the peninsulas. Michigan has the longest freshwater coastline of any political subdivision in the United States, being bordered by four of

12463-664: The simplest. For aliphatic compounds this is sometimes called the Finkelstein reaction , while for aromatic compounds it is known as the Halex process . Alkyl monofluorides can be obtained from alcohols and Olah reagent (pyridinium fluoride) or another fluoridating agents. The decomposition of aryldiazonium tetrafluoroborates in the Sandmeyer or Schiemann reactions exploit fluoroborates as F sources. Although hydrogen fluoride may appear to be an unlikely nucleophile, it

12584-418: The socioeconomic life of the United States and much of the world. With the growth, the auto industry created jobs in Detroit that attracted immigrants from Europe and migrants from across the United States, including both blacks and whites from the rural South . By 1920, Detroit was the fourth-largest city in the U.S.. Residential housing was in short supply, and it took years for the market to catch up with

12705-888: The south and east, were the Mascouten , the Menominee , the Miami , the Sac (or Sauk), and the Meskwaki (Fox) . The Wyandot were an Iroquoian-speaking people in this area; they were historically known as the Huron by the French, and were the historical adversaries of the Iroquois Confederation . French voyageurs and coureurs des bois explored and settled in Michigan in the 17th century. The first Europeans to reach what became Michigan were those of Étienne Brûlé 's expedition in 1622. The first permanent European settlement

12826-596: The state, marked by highway signs and the Polar-Equator Trail— along a line including Mission Point Light near Traverse City , the towns of Gaylord and Alpena in the Lower Peninsula and Menominee in the Upper Peninsula. With the exception of two tiny areas drained by the Mississippi River by way of the Wisconsin River in the Upper Peninsula and by way of the Kankakee - Illinois River in

12947-409: The top drugs. Examples include 5-fluorouracil , flunitrazepam (Rohypnol), fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine , and fluconazole . Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about

13068-746: The triflic acid) is a good leaving group in substitution reactions. Fluorocarbon substituents can enhance the Lewis acidity of metal centers. A premier example is " Eufod ," a coordination complex of europium(III) that features a perfluoroheptyl modified acetylacetonate ligand . This and related species are useful in organic synthesis and as "shift reagents" in NMR spectroscopy . Highly fluorinated substituents, e.g. perfluorohexyl (C 6 F 13 ) confer distinctive solubility properties to molecules, which facilitates purification of products in organic synthesis . This area, described as " fluorous chemistry," exploits

13189-623: The usefulness of fluorous phases and the use of PFOA in processing of fluoropolymers. In contrast to the aliphatic derivatives, perfluoroaromatic derivatives tend to form mixed phases with nonfluorinated aromatic compounds, resulting from donor-acceptor interactions between the pi-systems. Polymeric organofluorine compounds are numerous and commercially significant. They range from fully fluorinated species, e.g. PTFE to partially fluorinated, e.g. polyvinylidene fluoride ([CH 2 CF 2 ] n ) and polychlorotrifluoroethylene ([CFClCF 2 ] n ). The fluoropolymer polytetrafluoroethylene (PTFE/Teflon)

13310-598: The very southern portions of the state have tornado sirens to warn residents of approaching tornadoes. Farther north, in Central Michigan, Northern Michigan, and the Upper Peninsula, tornadoes are rare. The geological formation of the state is greatly varied, with the Michigan Basin being the most major formation. Primary boulders are found over the entire surface of the Upper Peninsula (being principally of primitive origin), while Secondary deposits cover

13431-512: The west, capped around by the Canadian province of Ontario to the north and east. The heavily forested Upper Peninsula is relatively mountainous in the west. The Porcupine Mountains , which are part of one of the oldest mountain chains in the world, rise to an altitude of almost 2,000 feet (610 m) above sea level and form the watershed between the streams flowing into Lake Superior and Lake Michigan. The surface on either side of this range

13552-497: The western part of the Upper Peninsula as a concession and formally entered the Union as a free state on January 26, 1837. The Upper Peninsula proved to be a rich source of lumber, iron, and copper. Michigan led the nation in lumber production from the 1850s to the 1880s. Railroads became a major engine of growth from the 1850s onward, with Detroit the chief hub . A second wave of French-Canadian immigrants settled in Michigan during

13673-432: The winter through the middle of February, the state is frequently subjected to heavy lake-effect snow . The state averages from 30 to 40 inches (76 to 102 cm) of precipitation annually; however, some areas in the northern lower peninsula and the upper peninsula average almost 160 inches (4,100 mm) of snowfall per year. Michigan's highest recorded temperature is 112 °F (44 °C) at Mio on July 13, 1936, and

13794-438: The world to the negative consequences of organofluorine compounds and motivated the development of new routes to organofluorine compounds. In 2002, the first C-F bond-forming enzyme, fluorinase , was reported. Only a few organofluorine compounds are acutely bioactive and highly toxic, such as fluoroacetate and perfluoroisobutene . Michigan Michigan ( / ˈ m ɪ ʃ ɪ ɡ ən / MISH -ig-ən )

13915-462: The year the stamp was first issued. A constitutional convention of assent was held to lead the territory to statehood. In October 1835 the people approved the constitution of 1835, thereby forming a state government. Congressional recognition was delayed pending resolution of a boundary dispute with Ohio known as the Toledo War . Congress awarded the "Toledo Strip" to Ohio. Michigan received

14036-549: Was an important center of industry-wide union organizing, such as the rise of the United Auto Workers . In 1920 WWJ (AM) in Detroit became the first radio station in the United States to regularly broadcast commercial programs. Throughout that decade, some of the country's largest and most ornate skyscrapers were built in the city. Particularly noteworthy are the Fisher Building , Cadillac Place , and

14157-466: Was announced, which Joseph H. Simons had developed in the 1930s to generate highly stable perfluorinated materials compatible with uranium hexafluoride . These new methodologies allowed the synthesis of C-F bonds without using elemental fluorine and without relying on metathetical methods. In 1957, the anticancer activity of 5-fluorouracil was described. This report provided one of the first examples of rational design of drugs. This discovery sparked

14278-418: Was formed in 1805, but some of the northern border with Canada was not agreed upon until after the War of 1812 . Michigan was admitted into the Union in 1837 as the 26th state, a free one . It soon became an important center of industry and trade in the Great Lakes region, attracting immigrants in the late 19th and early 20th centuries from many European countries . Immigrants from Finland , Macedonia , and

14399-438: Was founded in 1668 on the site where Père Jacques Marquette established Sault Ste. Marie, Michigan , as a base for Catholic missions. Missionaries in 1671–75 founded outlying stations at Saint Ignace and Marquette . Jesuit missionaries were well received by the area's Indian populations, with few difficulties or hostilities. In 1679, Robert Cavelier, Sieur de la Salle built Fort Miami at present-day St. Joseph . In 1691,

14520-577: Was founded in 1849, for the training of teachers. It was the fourth oldest normal school in the United States and the first U.S. normal school outside New England . In 1899, the Michigan State Normal School became the first normal school in the nation to offer a four-year curriculum. Michigan Agricultural College (1855), now Michigan State University in East Lansing , was founded as the first agricultural college in

14641-501: Was the third-largest city in Quebec province. During the American Revolutionary War , Detroit was an important British supply center. Most of the inhabitants were French-Canadians or American Indians, many of whom had been allied with the French because of long trading ties. Because of imprecise cartography and unclear language defining the boundaries in the 1783 Treaty of Paris , the British retained control of Detroit and Michigan after

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