`
`Ball-and-stick model of the
`
`hydroxyl (-OH) functional
`
`group in an alcohol molecule
`
`(R3COH). The three "R's"
`
`stand for carbon substituents
`
`or hydrogen atoms. [1]
`
`O
`/\./\
`
`R
`
`The hydroxyl (-OH)
`
`functional group with bond
`
`angle
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
`Page 0001
`Page 0001
`
`1f15
`
`5112015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`i A
`
`lcohol
`
`From Wikipedia, the free encyclopedia
`
`In chemistry, an alcohol is any organic compound in which the hydroxyl
`functional group (-O H) is bound to a saturated carbon atom.[2] The term
`alcohol originally referred to the primary alcohol ethyl alcohol (ethanol),
`the predominant alcohol in alcoholic beverages.
`
`The suffix -0[ appears in the IUPAC chemical name of all substances where
`the hydroxyl group is the functional group with the highest priority; in
`substances where a higher priority group is present the prefix hydroxy— will
`appear in the IUPAC name. The suffix -ol in non-systematic names (such as
`paracetamol or cholesterol) also typically indicates that the substance
`includes a hydroxyl functional group and, so, can be termed an alcohol. But
`many substances, particularly sugars (examples glucose and sucrose)
`contain hydroxyl functional groups without using the suffix. An important
`class of alcohols are the simple acyclic alcohols, the general formula for
`which is CnHZnHOH.
`
`Contents
`
`I
`
`1 Occurrence in nature
`
`I 2 Toxicity
`I 2.1 Treatment
`
`I 3 Nomenclature
`
`I 3.1 Systematic names
`I 3.2 Common names
`
`I 3.2.1 Alkyl chain variations in alcohols
`I 3.2.2 Simple alcohols
`I 3.2.3 Higher alcohols
`I 3.3 Etymology
`I 4 Physical and chemical properties
`I 5 Applications
`I 5.1 Alcoholic beverages
`I 5.2 Antifreeze
`
`5.3 Antiseptics
`5.4 Fuels
`
`5.5 Preservative
`
`5.6 Solvents
`
`I 6 Production
`
`6.1 Ziegler and 0x0 processes
`6.2 Hydration reactions
`6.3 Biological routes
`6.4 Laboratory synthesis
`I 6.4.1 Substitution
`
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`Alcohol - Wikipedia, the free encyclopedia
`
`I 6.4.2 Reduction
`
`I 6.4.3 Hydrolysis
`I 7 Reactions
`
`I 7.1 Deprotonation
`I 7.2 Nucleophilic substitution
`I 7.3 Dehydration
`I 7.4 Esterification
`
`I 7.5 Oxidation
`
`8 See also
`
`9 Notes
`
`10 References
`
`11 External links
`
`Occurrence in nature
`
`Alcohols have been found outside the Solar System where they can be found in low densities in star and
`planetary-system-forming regions of space.[3]
`
`
`
`
`
`J
`
`J
`
`Ball-and-stick model of tert—Amyl
`alCOhOL WhiCh is 20 times more
`intOXicating than Ethaml and like all
`tertiary alcohols, cannot be
`metabolised to toxic
`aldehydes.[4][5][6]
`
`Toxicity
`
`Ethanol is thought to cause harm partly as a result of direct damage to
`DNA caused by its metabolitesm
`
`Ethanol's toxicity is largely caused by its primary metabolite,
`acetaldehyde (systematically ethanal)[8][9] and secondary metabolite,
`[10][11][12]
`acetic acid.[9]
`Many primary alcohols are metabolized into
`aldehydes then to carboxylic acids whose toxicities are similar to
`acetaldehyde and acetic acid. Metabolite toxicity is reduced in rats
`fed N—acetylcysteine[8][13] and thiamineml
`
`Tertiary alcohols cannot be metabolized into aldehydesfls] and as a
`result they cause no hangover 0r toxicity through this mechanism.
`
`Some secondary and tertiary alcohols are less poisonous than ethanol
`because the liver is unable to metabolize them into toxic by-
`products.[16] This makes them more suitable for pharmaceutical use
`as the chronic harms are lower.[17] Ethchlorvynol and tert-amyl
`alcohol are tertiary alcohols which have seen both medicinal and recreational usellg]
`
`Other alcohols are substantially more poisonous than ethanol, partly because they take much longer to be
`metabolized and partly because their metabolism produces substances that are even more toxic. Methanol
`(wood alcohol), for instance, is oxidized to formaldehyde and then to the poisonous formic acid in the liver
`by alcohol dehydrogenase and formaldehyde dehydrogenase enzymes, respectively; accumulation of formic
`acid can lead to blindness or death.[19] Likewise, poisoning due to other alcohols such as ethylene glycol or
`
`diethylene glycol are due to then metabolites, whlch are also produced by alcohol dehy‘flgolggfigsefqC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
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`

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`5'1!2015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`Methanol itself, while poisonous (LD50 5628 mg/kg, oral, rat[22]), has
`a much weaker sedative effect than ethanol.
`
`'"E'fiéE-“"
`
`.____
`
`__ J:"—
`
`--
`
`.—
`
`Isopropyl alcohol is oxidized to form acetone by alcohol
`dehydrogenase in the liver but has occasionally been abused by
`[23][24]
`
`alcoholics, leading to a range of adverse health effects.
`
`'73-'- 5:: -
`- T, --
`" "
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`
`.
`
`-
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`
`Treatment
`
`An effective treatment to prevent toxicity after methanol 0r ethylene
`glycol ingestion is to administer ethanol. Alcohol dehydrogenase has
`a higher affinity for ethanol, thus preventing methanol from binding
`and acting as a substrate. Any remaining methanol will then have
`time to be excreted through the kidneys.[19][25][26]
`
`Most significant of the possible long-
`
`term effects of ethanol. In addition,
`
`in pregnant women, it causes fetal
`
`alcohol syndrome.
`
`Nomenclature
`
`Systematic names
`
`IUPAC nomenclature is used in scientific publications and where precise identification of the substance is
`important, especially in cases where the relative complexity of the molecule does not make such a systematic
`name unwieldy. In the IUPAC system, in naming simple alcohols, the name of the alkane chain loses the
`terminal "e" and adds "01", e.g., as in "methanol" and "ethan01".[27] When necessary, the position of the
`hydroxyl group is indicated by a number between the alkane name and the "ol": propan-l-ol for
`CH3CH2CH20H, propan-Z-ol for CH3CH(OH)CH3. If a higher priority group is present (such as an
`
`aldehyde, ketone, or carboxylic acid), then the prefix "hydroxy" is used,[27] e.g., as in 1-hydroxy-2-
`propanone (CH3C(O)CH2OH). [28]
`
`3:
`cwwm-DH
`CH”
`mm 1
`
`in“
`Wm?“
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`OH
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`will-[m CH:
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`nmm
`
`Some examples of simple alcohols and how to name them
`
`Common names
`
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`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
`Page 0003
`Page 0003
`
`3"15
`
`

`

`519015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`In other less formal contexts, an alcohol is often called with the name of the corresponding alkyl group
`followed by the word "alcohol", e.g., methyl alcohol, ethyl alcohol. Propyl alcohol may be n-propyl alcohol
`or isopropyl alcohol, depending on whether the hydroxyl group is bonded to the end or middle carbon on the
`straight propane chain. As described under systematic naming, if another group on the molecule takes
`priority, the alcohol moiety is often indicated using the "hydroxy-" prefix.
`
`Alcohols are then classified into primary, secondary (sec-, s-), and tertiary (tert-, t-), based upon the number
`of carbon atoms connected to the carbon atom that bears the hydroxyl functional group. (The respective
`numeric shorthands 1°, 2°, and 3° are also sometimes used in informal settings.[29]) The primary alcohols
`have general formulas RCHzOH; methanol (CH3OH is the simplest primary alcohol (R=H), and after it,
`
`ethanol (R=CH3). Secondary alcohols can be referred to with the shorthand RR'CHOH; 2-propanol is the
`
`simplest example (R=R'=CH3). Tertiary alcohols can be referred to with the shorthand RR'R"COH; tert-
`
`butanol (2-methylpropan-2-ol) is the simplest example (R=R'= "=CH3). In these shorthands, R, R', and R"
`
`represent substituents, alkyl or other attached, generally organic groups.
`
`.
`_
`.
`_
`_
`.
`http:fien.wlklpedla.orgwkIlNcohoHfl-II her_alcohols
`9
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
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`Exhibit 1016
`Page 0004
`Page 0004
`
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`
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`

`5112015
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`Alcohol - Wikipedia, the free encyclopedia
`
`Chemical Formula
`
`IUPAC Name
`
`Common Name
`
`CH3OH
`
`CZHSOH
`
`C3H7OH
`
`C4H90H
`
`C5H110H
`
`C 16H330H
`
`C2H4(OH)2
`
`C3H6(OH)2
`
`C3H5(OH)3
`
`C4H6(OH)4
`
`C5H7(OH)5
`
`C6Hg(0H)6
`
`C7H9(OH)7
`
`C3H50H
`
`C 10H 170H
`
`C3H3OH
`
`Monohydrz’c alcohols
`
`Methanol
`
`Ethanol
`
`Wood alcohol
`
`Alcohol
`
`lsopropyl alcohol
`
`Rubbing alcohol
`
`Butyl alcohol
`
`Pentanol
`
`Hexadecan— 1 -ol
`
`Polyhya’rz'c alcohols
`
`Ethane-1,2-diol
`
`Propane-1,2-di01
`
`Butanol
`
`Amyl alcohol
`
`Cetyl alcohol
`
`Ethylene glycol
`
`Propylene Glycol
`
`Propane-1,2,3-triol
`
`Glycerol
`
`Butane-1,2,3,4-tetraol
`
`Erythritol, Threitol
`
`Pentane- l ,2,3,4,5-pentol
`
`Xylitol
`
`Hexane-l,2,3,4,5,6-hexol
`
`Mannitol, Sorbitol
`
`Heptane- 1 23,45 ,6,7-hept01
`
`Volemitol
`
`Unsaturated aliphatic alcohols
`
`Prop-2-ene- l -01
`
`Allyl alcohol
`
`3,7-Dimethylocta—2,6-dien— l-ol
`
`Geraniol
`
`Prop-2-in- l -01
`
`Propargyl alcohol
`
`Alicyclic alcohols
`
`C6H6(0H)6
`
`Cyclohexane- l ,2,3,4,5,6-hex01
`
`C10H190H
`
`2 - (2-propyl)—5-methyl-cyclohexane-l-ol
`
`Inositol
`
`Menthol
`
`Alkyl chain variations in alcohols
`
`Short-chain alcohols have alkyl chains of 1-3 carbons. Medium-chain alcohols have alkyl chains of 4-7
`carbons. Long-chain alcohols (also known as fatty alcohols) have alkyl chains of 8-21 carbons, and very
`long-chain alcohols have alkyl chains of 22 carbons or longer.[30]
`
`Simple alcohols
`
`”Simple alcohols" appears to be a completely undefined term. However, simple alcohols are often referred to
`by common names derived by adding the word "alcohol" to the name of the appropriate alkyl group. For
`instance, a chain consisting of one carbon (a methyl group, CH3) with an OH group attached to the carbon is
`
`httpjllenwi kipediaorgw kilAl coholtfl-ligherjlcohds
`
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`

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`
`called "methyl alcohol" while a chain of two carbons (an ethyl group, CHZCH3) with an OH group connected
`
`to the CH2 is called "ethyl alcohol.” For more complex alcohols, the IUPAC nomenclature must be used.[31]
`
`Simple alcohols, in particular ethanol and methanol, possess denaturing and inert rendering properties,
`leading to their use as anti-microbial agents in medicine, pharmacy, and industry.
`
`Higher alcohols
`
`Encyclopaedia Britannica states, "The higher alcohols - those containing 4 to 10 carbon atoms — are
`somewhat viscous, or oily, and they have heavier fruity odours. Some of the highly branched alcohols and
`"[32]
`
`many alcohols containing more than 12 carbon atoms are solids at room temperature.
`
`Like ethanol, butanol can be produced by fermentation processes. Saccharomyces yeast are known to
`produce these higher alcohols at temperatures above 75 °F (24 °C). The bacterium Clostrz'dz'um
`acetobutylz'cum can feeds on cellulose to produce butanol on an industrial scale.
`
`Etymology
`
`The word alcohol appears in English as a term for a very fine powder in the sixteenth century. It was
`borrowed from French, which took it from medical Latin.
`
`Ultimately the word is from the Arabic JAS (al—kuhl, "kohl, a powder used as an eyeliner"). Al- is the Arabic
`definitive article, equivalent to the in English; alcohol was originally used for the very fine powder produced
`by the sublimation of the natural mineral stibnite to form antimony sulfide Sb2S3 (hence the essence or
`
`"spirit" of the substance), which was used as an antiseptic, eyeliner, and cosmetic (see kohl (cosmetics)).
`Bartholomew Traheron, in his 1543 translation of John of Vigo, introduces the word as a term used by
`”barbarous" (Moorish) authors for ”fine powder." Vigo wrote: the barbarous auctours use alcohol, or (as 1
`finale it sometymes wrjyten) alcofoll, for moostfine poudre.
`
`The 1657 Lexicon Chymicum (http://booksgoogle.com/books/about/Lexicon_Chymicum.html?
`id=d645AAAAcAAJ) by William Johnson glosses the word as antimonium sive stibium. By extension, the
`word came to refer to any fluid obtained by distillation, including "alcohol of wine,” the distilled essence of
`wine. Libavius in Alchymia (1594) refers to vini alcohol vel vinum alcalisatum. Johnson (1657) glosses
`alcohol vinz’ as quando omnis superfluitas vini a vino separatur, ita at accensum ardeat donec totum
`consumatur, nihilquefoecum autphlegmatis infundo remaneat. The word's meaning became restricted to
`”spirit of wine" (the chemical known today as ethanol) in the 18th century and was extended to the class of
`substances so-called as "alcohols" in modern chemistry after 1850.
`
`The current Arabic name for alcohol (ethanol) is chill al-gawl — properly meaning "spirit" or "demon" — with
`the sense "the thing that gives the wine its headiness" (in the Qur'an sura 37 verse 47).[33] The term ethanol
`was invented 1838, modeled on the German word athyl (Liebig), which is in turn based on Greek aither
`ether and hyle "stuff."[34]
`
`Physical and chemical properties
`
`httpjllenwi kipediaorgw kilAl coholtfl-Iigherjlcohds
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
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`
`W
`
`

`

`51:2015
`
`Alcohol - Wikipedia. the free encyclopedia
`
`Alcohols have an odor that is often described as “biting” and as “hanging” in the nasal passages. Ethanol has
`a slightly sweeter (or more fruit-like) odor than the other alcohols.
`
`In general, the hydroxyl group makes the alcohol molecule polar. Those groups can form hydrogen bonds to
`one another and to other compounds (except in certain large molecules where the hydroxyl is protected by
`steric hindrance of adjacent groups[35]). This hydrogen bonding means that alcohols can be used as protic
`solvents. Two opposing solubility trends in alcohols are: the tendency of the polar OH to promote solubility
`in water, and the tendency of the carbon chain to resist it. Thus, methanol, ethanol, and propanol are miscible
`in water because the hydroxyl group wins out over the short carbon chain. Butanol, with a four-carbon chain,
`is moderately soluble because of a balance between the two trends. Alcohols of five or more carbons such as
`pentanol and higher are effectively insoluble in water because of the hydrocarbon chain's dominance. All
`simple alcohols are miscible in organic solvents.
`
`Because of hydrogen bonding, alcohols tend to have higher boiling points than comparable hydrocarbons
`and ethers. The boiling point of the alcohol ethanol is 78.29 °C, compared to 69 °C for the hydrocarbon
`hexane (a common constituent of gasoline), and 34.6 °C for diethyl ether.
`
`Alcohols, like water, can show either acidic or basic properties at the -OH group. With a pKa of around 16-
`
`19, they are, in general, slightly weaker acids than water, but they are still able to react with strong bases
`such as sodium hydride or reactive metals such as sodium. The salts that result are called alkoxides, with the
`
`general formula RO_ M+.
`
`Meanwhile, the oxygen atom has lone pairs of nonbonded electrons that render it weakly basic in the
`presence of strong acids such as sulfuric acid. For example, with methanol:
`
`”axe
`H1
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`Alcohols can also undergo oxidation to give aldehydes, ketones, or carboxylic acids, or they can be
`dehydrated to alkenes. They can react to form ester compounds, and they can (if activated first) undergo
`nucleophilic substitution reactions. The lone pairs of electrons on the oxygen of the hydroxyl group also
`makes alcohols nucleophiles. For more details, see the reactions of alcohols section below.
`
`As one moves from primary to secondary to tertiary alcohols with the same backbone, the hydrogen bond
`strength, the boiling point, and the acidity typically decrease.
`
`Applications
`
`Alcohol has a long history of several uses worldwide. It is found in alcoholic beverages sold to adults, as
`fuel, and also has many scientific, medical, and industrial uses. The term alcohol-free is often used to
`describe a product that does not contain alcohol. Some consumers of some commercially prepared products
`may view alcohol as an undesirable ingredient, particularly in products intended for children.
`
`httpjflenwi kipediacrgw RUN cohom-Iigherjlcohols
`
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`Exhibit 1016
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`Page 0007
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`
`ms
`
`

`

`51:2015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`Alcoholic beverages
`
`Alcoholicbeverages,typicallycontaining3—40%ethanolbyvolume,
`
`have been produced and consumed by humans since pre-historic times.
`
`Other alcohols such as 2-methyl-2-butanol (found in beer) and y-
`hydroxybutyric acid (GHB) are also consumed by humans for their
`psychoactive effects
`
`Antifreeze
`
`I;
`
`I
`
`fill
`
`3;
`
`Total recorded alcohol per capita
`consumption (15+), in litres of
`
`pure alcohol[36]
`
`A 50% v/v (by volume) solution of ethylene glycol in water is commonly used as an antifreeze.
`
`Antiseptics
`
`Ethanol can be used as an antiseptic to disinfect the skin before injections are given, often along with iodine.
`Ethanol-based soaps are becoming common in restaurants and are convenient because they do not require
`drying due to the volatility of the compound. Alcohol based gels have become common as hand sanitizers.
`
`Fuels
`
`Some alcohols, mainly ethanol and methanol, can be used as an alcohol fuel. Fuel performance can be
`increased in forced induction internal combustion engines by injecting alcohol into the air intake after the
`turbocharger or supercharger has pressurized the air. This cools the pressurized air, providing a denser air
`charge, which allows for more fuel, and therefore more power.
`
`Preservative
`
`Alcohol is often used as a preservative for specimens in the fields of science and medicine.
`
`Solvents
`
`Hydroxyl groups (-OH), found in alcohols, are polar and therefore hydrophilic (water loving) but their
`carbon chain portion is non-polar which make them hydrophobic. The molecule increasingly becomes
`overall more nonpolar and therefore less soluble in the polar water as the carbon chain becomes longer.[37]
`Methanol has the shortest carbon chain of all alcohols (one carbon atom) followed by ethanol (two carbon
`atoms.)
`
`Alcohols have applications in industry and science as reagents or solvents. Because of its relatively low
`toxicity compared with other alcohols and ability to dissolve non-polar substances, ethanol can be used as a
`solvent in medical drugs, perfumes, and vegetable essences such as vanilla. In organic synthesis, alcohols
`serve as versatile intermediates.
`
`Production
`
`Ziegler and 0x0 processes
`
`httpjflenwi kipediaorgw RUN coholifl-Iigherjlcohols
`
`1,4 GROUP, INC.
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`
`ms
`
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`

`519015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`In the Ziegler process, linear alcohols are produced from ethylene and triethylaluminium followed by
`oxidation and hydrolysis.[38] An idealized synthesis of l-octanol is shown:
`
`A1(C2H5)3 + 9 C2H4 —* A1(C8Hi7)3
`
`A1(C8H17)3 + 3 O + 3 H20 —> 3 HOC8H17 + AI(OH)3
`
`The process generates a range of alcohols that are separated by distillation.
`
`Many higher alcohols are produced by hydroformylation of alkenes followed by hydrogenation. When
`applied to a terminal alkene, as is common, one typically obtains a linear alcohol: [38]
`
`RCH=CH2 + H2 + CO —> RCHzCHzCHO
`
`RCH2CH2CHO + 3 H2 —> RCHzCHzCHon
`
`Such processes give fatty alcohols, which are useful for detergents.
`
`Hydration reactions
`
`Low molecular weight alcohols of industrial importance are produced by the addition of water to alkenes.
`Ethanol, isopropanol, 2-butanol, and tert-butanol are produced by this general method. Two implementations
`are employed, the direct and indirect methods. The direct method avoids the formation of stable
`intermediates, typically using acid catalysts. In the indirect method, the alkene is converted to the sulfate
`ester, which is subsequently hydrolyzed. The direct hydration using ethylene (ethylene hydration)[39] or other
`alkenes from cracking of fractions of distilled crude oil.
`
`Hydration is also used industrially to produce the diol ethylene glycol from ethylene oxide.
`
`Biological routes
`
`Ethanol is obtained by fermentation using glucose produced from sugar from the hydrolysis of starch, in the
`presence of yeast and temperature of less than 37 °C to produce ethanol. For instance, such a process might
`proceed by the conversion of sucrose by the enzyme invertase into glucose and fructose, then the conversion
`of glucose by the enzyme zymase into ethanol (and carbon dioxide).
`
`Several of the benign bacteria in the intestine use fermentation as a form of anaerobic metabolism. This
`metabolic reaction produces ethanol as a waste product, just like aerobic respiration produces carbon dioxide
`and water. Thus, human bodies contain some quantity of alcohol endogenously produced by these bacteria.
`In rare cases, this can be sufficient to cause "auto-brewery syndrome" in which intoxicating quantities of
`alcohol are produced.[40] [411W]
`
`Laboratory synthesis
`
`Several methods exist for the preparation of alcohols in the laboratory.
`
`Substitution
`
`_
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`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
`Page 0009
`Page 0009
`
`94'15
`
`

`

`5112015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`Primary alkyl halides react with aqueous NaOH or KOH mainly to primary alcohols in nucleophilic aliphatic
`substitution. (Secondary and especially tertiary alkyl halides will give the elimination (alkene) product
`instead). Grignard reagents react with carbonyl groups to secondary and tertiary alcohols. Related reactions
`are the Barbier reaction and the Nozaki-Hiyama reaction.
`
`Reduction
`
`Aldehydes or ketones are reduced with sodium borohydride or lithium aluminium hydride (after an acidic
`workup). Another reduction by aluminiumisopropylates is the Meerwein—Ponndorf—Verley reduction. Noyori
`asymmetric hydrogenation is the asymmetric reduction of B-keto-esters.
`
`Hydrolysis
`
`Alkenes engage in an acid catalysed hydration reaction using concentrated sulfuric acid as a catalyst that
`gives usually secondary or tertiary alcohols. The hydroboration-oxidation and oxymercuration—reduction of
`alkenes are more reliable in organic synthesis. Alkenes react with NBS and water in halohydrin formation
`reaction. Amines can be converted to diazonium salts, which are then hydrolyzed.
`
`The formation of a secondary alcohol via reduction and hydration is shown:
`
`0
`NaBH
`0H
`H2804
`RK—“H WW
`
`Reactions
`
`Deprotonation
`
`Alcohols can behave as weak acids, undergoing deprotonation. The deprotonation reaction to produce an
`alkoxide salt is performed either with a strong base such as sodium hydride or n-butyllithium or with sodium
`or potassium metal.
`
`2 R—OH + 2 NaH —> 2 11—0112? + 2H2T
`
`2 R—OH + 2 Na —> 2 R—ONa+ + H2
`
`2 CH3CH2-OH + 2 Na —> 2 CH3-CH2-O_Na+ + H2T
`
`Water is similar in pKa to many alcohols, so with sodium hydroxide there is an equilibrium set-up, which
`
`usually lies to the left:
`
`R-OH + NaOH = R—O‘Na+ + H20 (equilibrium to the left)
`
`It should be noted, however, that the bases used to deprotonate alcohols are strong themselves. The bases
`used and the alkoxides created are both highly moisture-sensitive chemical reagents.
`
`hfipzflenwikipediaorg’wikilAlcoholWigher_alcohols
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
`Page 0010
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`
`10315
`
`

`

`51i2015
`
`Alcohol - Wikipedia, the free encyclopedia
`
`The acidity of alcohols is also affected by the overall stability of the alkoxide ion. Electron-withdrawing
`groups attached to the carbon containing the hydroxyl group will serve to stabilize the alkoxide when
`formed, thus resulting in greater acidity. On the other hand, the presence of electron-donating group will
`result in a less stable alkoxide ion formed. This will result in a scenario whereby the unstable alkoxide ion
`formed will tend to accept a proton to reform the original alcohol.
`
`With alkyl halides alkoxides give rise to ethers in the Williamson ether synthesis.
`
`Nucleophilic substitution
`
`The OH group is not a good leaving group in nucleophilic substitution reactions, so neutral alcohols do not
`
`react in such reactions. However, if the oxygen is first protonated to give R—OH2+, the leaving group (water)
`
`is much more stable, and the nucleophilic substitution can take place. For instance, tertiary alcohols react
`with hydrochloric acid to produce tertiary alkyl halides, where the hydroxyl group is replaced by a chlorine
`atom by unimolecular nucleophilic substitution. If primary or secondary alcohols are to be reacted with
`hydrochloric acid, an activator such as zinc chloride is needed. In alternative fashion, the conversion may be
`performed directly using thionyl chloridem
`
`:unc.HC| H3: III:H3
`"
`£13.,
`
`H3: {FHa
`.33..
`
`DH [3,“:
`H33
`E-Mnflpmpan-Z-ol
`A martian? alumni
`
`-
`
`H3:
`Ema yield
`
`CI
`
`
`CHECHECHECHfiHECHECHEOH
`cuacH2cH2I3H2cHECI-I2I:H2I;I
`+ 5am
`+502): HCI
`.
`1 h
`1
`- minnoi. a primary alcohol
`rm pale
`
`”a”
`
`Alcohols may, likewise, be converted to alkyl bromides using hydrobromic acid or phosphorus tribromide,
`for example:
`
`3 R-OH + PBI'3 —> 3 RBI + H3PO3
`
`In the Barton-McCombie deoxygenation an alcohol is deoxygenated to an alkane with tributyltin hydride or
`a trimethylborane-water complex in a radical substitution reaction.
`
`Dehydration
`
`Alcohols are themselves nucleophilic, so R—OH2+ can react with ROH to produce ethers and water in a
`
`dehydration reaction, although this reaction is rarely used except in the manufacture of diethyl ether.
`
`More useful is the El elimination reaction of alcohols to produce alkenes. The reaction, in general, obeys
`Zaitsev's Rule, which states that the most stable (usually the most substituted) alkene is formed. Tertiary
`alcohols eliminate easily at just above room temperature, but primary alcohols require a higher temperature.
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
`Exhibit 1016
`Page 0011
`Page 0011
`
`11:15
`
`This is a diagram of acid catalysed dehydration of ethanol to produce ethene:
`
`""
`
`(3—6
`
`,H
`H,
`‘H
`H’
`+ H20 + H
`
`H
`I,
`I
`'- H C C
`I
`I
`H
`H
`
`H
`
`H
`H
`,H
`I
`I
`H—C—C—O: —--
`I
`I
`D
`H
`H
`
`t
`
`H
`H
`I (A.
`I
`H—C--C—O—~H
`l
`I
`i
`H
`H
`H
`
`H
`
`hfipzflenwikipediacrgwkiI'AIcohoiifl-iigherjlcohois
`
`

`

`51'1l2015
`
`Alcohol - Wikipedia. the free encyclopedia
`
`A more controlled elimination reaction is the ChugaeV elimination with carbon disulfide and iodomethane.
`
`Esterification
`
`To form an ester from an alcohol and a carboxylic acid the reaction, known as Fischer esterification, is
`usually performed at reflux with a catalyst of concentrated sulfuric acid:
`
`R—OH + R'-COOH —> R'—COOR + H20
`
`In order to drive the equilibrium to the right and produce a good yield of ester, water is usually removed,
`either by an excess of H2804 or by using a Dean-Stark apparatus. Esters may also be prepared by reaction of
`
`the alcohol with an acid chloride in the presence of a base such as pyridine.
`
`Other types of ester are prepared in a similar manner — for example, tosyl (tosylate) esters are made by
`reaction of the alcohol with p-toluenesulfonyl chloride in pyridine.
`
`Oxidation
`
`Primary alcohols (R—CHz-OH) can be oxidized either to aldehydes (R—CHO) or to carboxylic acids (R-
`
`COzH), while the oxidation of secondary alcohols (RIRZCH-OH) normally terminates at the ketone
`
`(R1R2C=O) stage. Tertiary alcohols (R1R2R3C-OH) are resistant to oxidation.
`
`The direct oxidation of primary alcohols to carboxylic acids normally proceeds Via the corresponding
`aldehyde, which is transformed Via an aldehyde hydrate (R—CH(OH)2) by reaction with water before it can
`
`be further oxidized to the carboxylic acid.
`
`R—CHFUH
`
` in] P +ng
`
`up H—G‘
`H
`
`
`
`—H2Cl
`
`‘i'H
`H'Q'DH
`H
`
`[D]
`
`P
`b Fl—FCx
`OH
`
`piimery aleehel
`
`aldehyde
`
`aldehyde hydrate
`
`earhdxylic acid
`
`Mechanism of oxidation of primary alcohols to carboxylic acids Via aldehydes and
`
`aldehyde hydrates
`
`Reagents useful for the transformation of primary alcohols to aldehydes are normally also suitable for the
`oxidation of secondary alcohols to ketones. These include Collins reagent and Dess-Martin periodinane. The
`direct oxidation of primary alcohols to carboxylic acids can be carried out using potassium permanganate or
`the Jones reagent.
`
`See also
`
`2-Methyl-2-butanol
`Blood alcohol content
`
`Breathalyzer
`Cooking with alcohol
`Enol
`
`Ethanol fuel
`- 1:0th annlflnl
`hfipzllenwi kipediaorgfwi kilAlcohoimigheLaicohols
`
`1,4 GROUP, INC.
`1,4 GROUP, INC.
`Exhibit 1016
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`Page 0012
`Page 0012
`
`12:15
`
`

`

`5112015
`
`1 any albUllUl
`
`Alcohol - Wikipedia, the free encyclopedia
`
`History of alcoholic beverages
`List of countries by alcohol consumption
`Phenols
`
`Polyol
`Rubbing alcohol
`Sugar alcohol
`Surrogate alcohol
`Transesterification
`
`Notes
`
`1.
`
`2.
`
`"alcohols" (http://goldbook.iupac.org/A00204.html). IUPAC Gold Book. Retrieved 16 December 2013.
`IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:
`(2006—) "Alcohols (http://goldbook. iupac. org/A00204.html) ".
`. Charnley, S. B.; Kress, M. E.; Tielens, A. G. G. M.; Millar, T. J. (1995). "Interstellar Alcohols". Astrophysical
`Journal 448: 232. Bibcode:1995ApJ...448..232C (http://adsabs.harvard.edu/abs/ 1995ApJ ...448..232C).
`doi:10.1086/175955 (https://dx.doi.org/10.1086%2F175955).
`4. Hans Brandenberger & Robert A. A. Maes, ed. (1997). Analytical Toxicology for Clinical, Forensic and
`Pharmaceutical Chemists (http://books. google.com/books?
`id=ZhYtynyC4kAC&pg=PA401#v=onepage&q&f=false). p. 401. ISBN 3-11-010731-7.
`5. D. W. Yandell et a1. (1888). "Amylene hydrate, a new hypnotic" (http://books.google.com/books?
`id=Ra5YAAAAMAAJ&pg=PA88#v=onepage). The American Practitioner and News (Lousville KY: John P.
`Morton & C0) 5: 88—89.
`6. Carey, Francis. Organic Chemistry
`(http://www.mhhe.com/physsci/chemistry/carey/student/olc/ch150xidationalcoholshtml) (4 ed.).
`ISBN 0072905018. Retrieved 5 February 2013.
`7. Brooks, P. J. (1997). "DNA Damage, DNA Repair, and Alcohol Toxicity-A Review". Alcoholism: Clinical and
`Experimental Research 21 (6): 1073. doi:10.1111/j.1530-0277.1997.tb04256.x
`(https://dx.doi.org/10.1111%2Fj.1530-0277.1997.tb04256.X).
`8. Fowkes, Steven (13 December 1996). "Living with alcohol" (http://www.ceri.com/alcohol.htm). Smart Drug News
`{http://wwwceri.com/sdnewshtm) 5. Retrieved 2 March 2012.
`9. Melton, Lisa. "What's your poison" (http://www.cheerzhangover.com/Cheerz_ATH—NewScience.pdf) (PDF). New
`Scientist. Archived from the original (http://Www.newscientist.com/article/mg19325901.700-whats-your—
`poisonhtml) on 21 February 2012. Retrieved 10 February 2007.
`10. Maxwell, C. R.; Spangenberg, R. J .; Hoek, J. B.; Silberstein, S. D.; Oshinsky, M. L. (2010). Skoulakis,
`Efthimios M. C, ed. "Acetate Causes Alcohol Hangover Headache in Rats"
`(https://www.ncbi.nlm.nih.g0v/pmc/articles/PMC3013144). PLoS ONE 5 (12): e15963.
`doi:10.1371/j0urna1.p0ne.0015963 (https://dx.doi.org/10.1371%2Fjournalpone.0015963). PMC 3013144
`(https://www.ncbi.nlm.nih.gov/pmc/articlesmMC3013144). PMID 21209842
`(https ://www.ncbi.nlm.nih. g0v/pubmed/21209842).
`11. Ramachandra Murty, B (1 October 2004). "The Biochemistry of Alcohol Toxicity"
`(http://webcitation.org/6A3ijpaK). Archived from the original
`(http://www.ias.ac.in/resonance/Oct2004/pdf/Oct2004p41-47.pdf) (PDF) on 20 August 2012. Retrieved 21 February
`2012.
`
`12. Cassarett, Lewis; Doull, John (1986). Toxicology.‘ The Basic Science ofPoisons (3rd ed.) pp. 648—653.
`13. Ozaras, R.; Tahan, V.; Aydin, S.; Uzun, H.; Kaya, S.; Senturk, H. (2003). "N—acetylcysteine attenuates alcohol-
`induced oxidative stress in the rat". Worldjournal ofgastroenterology .‘ WJG 9 (1): 125—128. PMID 12508366
`(https ://www.ncbi.nlm.nih. gov/pubmed/12508366).
`14. "Protection against Acetaldehyde Toxicity in the rat byl—cysteine, thiamin and]-2-Methylthiazolidine-4-carboxylic
`acid". Agents andActions 4 (2): 125—130. 1974. doi:10.1007/BF01966822
`1,4 GROUP, INC.
`(https://dx.d0i.0rg/10.1007%2FBF01966822). PMID 4842541 (https://www.ncbi.nlm.nih,gcgkmbnem4254l).
`Exhibit 1016
`Exhibit 1016
`hfipzllenwikipediacrg’wikilAlcoholtfl-Iigherjlcohols
`1315
`Page 0013
`Page 0013
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`

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`Alcohol - Wikipedia. the free encyciopedia
`
`15. Collins, A. S.; Sumner, S. C.; Borghoff, S. J .; Medinsky, M. A. (1999). ”A physiological model for tert—amyl
`methyl ether and tert—amyl alcohol: Hypothesis testing of model structures". Toxicological sciences .' an oficial
`journal of the Society of Toxicology 49 (1): 15—28. doi:10.1093/toxsci/49.1.15
`(https://dx.doi.org/10. 1093%2Ftoxsci%2F49. 1. 15). PMID 10367338
`(https://www.ncbi.nlm.nih.gov/pubmed/10367338).
`16. "oxidation of alcohols" (http://www.chemguideco.uk/organicprops/alcohols/oxidation.html). chemguide. co. uk.
`17. Hirsh, H. L.; Orsinger, W. H. (1952). "Methylparafynol--a new type hypnotic. Preliminary report on its
`therapeutic effi