Experimental
`Organic 1
`Chemistry
`
`
`
`A Miniscale and Microscale Approach
`
`FIFTH EDITION
`
`
`
`John C. Gilbert
`
`Santa Clara University
`
`Stephen F. Martin
`
`University of Texas at Austin
`
`,"".; BROOKS/COLE
`It CENGAGE Learning"
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`SteadyMed - Exhibit 1018 - Page 1
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`art
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`SteadyMed - Exhibit 1018 - Page 1
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`;‘. BROOKS/COLE
`llr CENGAGELearning'
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`© 2011 Cengage Learning
`Experimental Organic Chemistry,
`Fifth Edition
`
`John C. Gilbert and Stephen F. Martin
`
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`SteadyMed - Exhibit 1018 - Page 2
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`SteadyMed - Exhibit 1018 - Page 2
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`Chapter 3 I Solids Recrystallization and Mailing Points
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`113
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`27. In the process of a recrystallization, if crystals do not form upon cooling the
`solution, it is often recommended that the inside of the flask be scratched at
`the air—liquid interface with a glass stirring rod. What purpose does this serve,
`and how does it Work? What else might be done to induce crystallization?
`28. Should some loss of sample mass be expected even after the most carefully
`executed recrystallization? Explain.
`-
`29. In general, what solvent should be used to rinse the filter cake during the vac—
`U_U.tI1 filtration step of a recrystallization? Should this solvent be cooled prior to
`use?
`
`30. Why do you seldom see high-boiling solvents used as recrystallization
`solvents?
`
`31. At the end of a recrystallization, where should the impurities be located?
`32. A student has been asked to recrystallize 1.0 g of impure stilbene from
`ethanol. Provide a set of standard step—by-step instructions for recrystalliza-
`tion of this sample so as to maximize the purity and yield obtained.
`33. An important product from a multistep synthesis must be recrystallized to
`remove‘ a small amount of an impurity. However, all
`the available
`solvents each individually fail to be suitable recrystallization solvents. Offer a
`. solution to this problem using only the available solvents. (Hint: Consider
`binary solvents.)
`34. A suspension of decolorizing carbon (charcoal) is often administered to poison
`victims.
`
`a. Speculate on the purpose decolorizing carbon serves in this particular
`
`used in a recrystallization.)
`b. How is the charcoal ultimately removed from the victim?
`
`3.3 PHYSICAL CONSTANTSI MELTING POINTS
`Physical Constants
`Physical constants of compounds are numerical values associated with measur-
`0
`able properties of these substances. These properties are invariant and are useful
`‘J See more on Melting Point
`in the identification and characterization of substances encountered in the labo~
`ratory so long as accurate measurements are made under specified conditions
`such as temperature and pressure. Physical constants are useful only in the iden-
`tification of previously known compounds, however, because it is not possible to
`predict the values of such properties accurately. Among the more frequently
`measured physical properties of organic compounds are melting point (mp),
`boiling point (bp), index of refraction (I1), density (cl), specific rotation ([011]),
`and solubility. Melting points, discussed below, boiling points, described in Sec-
`tion 42, and solubilities, outlined in Section 3.2, are the properties most com-
`monly encountered. Index of refraction and density are mentioned in Chapter 25.
`Specific rotation is discussed in Chapters 7 and 23 but applies only to molecules
`that are optically active. Whether the substance is known or unknown, such val-
`ues, along with other properties like color, odor, and crystal form, should be
`recorded in the laboratory notebook.
`The values of one or two of the common physical properties may be identical
`' for more than one compound, but it is most unlikely that values of several such
`
`SteadyMed - Exhibit 1018 - Page 3
`© 2011 Cengage Learning. All Rights Reserved. May not be scanned, ooplecl or duplicated, or posted to a publicly accessible website, in whole or in part.
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`SteadyMed - Exhibit 1018 - Page 3
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`114
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`Experimental Organic Chemistry I Gilbert and Martin
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`Melting Point of 2: Pure
`Substance
`
`Effect of Impurities an
`Melting Points
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`ll
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`properties will be the same for two different compounds. Consequently, a list of
`physical constants is a highly useful way to characterize a substance. Extensive
`compilations of the physical constants are available (Chap. 26). One of the most
`convenient is the CRC Handbook of Chemistry and Physics, which contains a tabula-
`tion of the physical constants and properties of a large number of inorganic and
`organic compounds. The Handbook of Tables for Organic Compounds is especially use-
`ful for organic compounds. Neither of these books is comprehensive; rather, they
`contain entries for only the more common organic and inorganic substances. So
`many compounds are known that multi-volume sets of books are required to list
`their physicai properties (Chap. 26).
`
`The melting point of a substance is defined as the temperature at which the liquid
`and solid phases exist in equilibrium with one another without change of temper-
`ature. Ideally, addition of heat to a mixture of the solid and liquid phases of a pure
`substance at the melting point will cause no rise in temperature until all the solid
`has melted. Conversely, removal of heat from the equilibrium mixture will pro-
`duce no decrease in temperature until all the liquid solidifies. This means that the
`melting and freezing points of a pure substance are identical.
`The melting point is expressed as the temperature range over which the solid
`starts to melt and then is completely converted to liquid. Consequently, rather
`than a melting point, what is actually measured is a melting range, although the
`two terms are used interchangeably. If a crystalline substance is pure, it should
`melt over a narrow or sharp range, which will normally be no more than 1 ‘’C if
`the melting point is determined carefully. The melting ranges reported for many-
`"pure” compounds may be greater than 1 °C because the particular compound
`was not quite pure or the melting point was not measured properly. The process
`of melting may actually begin by ”softening,” as evidenced by an apparent
`shrinking of the solid, but such softening is difficult to observe. Thus, for our
`purposes, the start of melting is defined as the temperature at which the first tiny
`droplet of liquid can be detected. Note that it is improper and inexact to report a
`single temperature, such as 118 °C, for a melting point; rather, a range of 117-119 "C
`or 117.5~118.0 “C, for example, should be recorded.
`
`Many solid substances prepared in the organic laboratory are initially impure, so
`the effect of impurities on melting-point ranges deserves further discussion.
`Although this topic is discussed in freshman chemistry textbooks, a brief review
`of its basic principles is given here.
`The presence of an impurity generally decreases the melting point of a pure solid.
`This is shown graphically by the melting~point—cornposition diagram of Figure 3.1,
`in which points a and la represent the melting points of pure A and B, respectively.
`Point E is called the eutectic point and is determined by the equilibrium composi-
`tion at which A and B melt in constant ratio. In Figure 3.1, this ratio is 60 mol % A
`and 40 mo} "/o B; an impure solid composed of A and B in this ratio would be called
`a eutectic mixture. The temperature at the eutectic point is designated by e.
`Now consider the result of heating a solid mixture composed of 80 mol "/0 A and
`20 mol "/2 B, a sample that might be considered as ”impure A.” As heat is applied to
`the solid, its temperature will rise. When the temperature reaches e, A and B will both
`begin to melt in the constant ratio defined by the composition at the eutectic point.
`Once all of the ”impurity” B has melted, only solid A will be left in equilibrium with
`the melt. The remaining solid A will continue to melt as additional heat is supplied,
`and the percentage of A in the melt will increase, changing the composition of the
`
`© 2011 Cengage Learning. All Rights Fieserved. May not be scanned, copied or duplicated. or posted to a g§gJgigk,hfi9tggeLbE)\get{fiite1 511vgigle;g'g'rg mart.
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`Chapter 3 I Solids Recrystallization and Melting Points
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`115
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`A“W:
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`.
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`I.
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`Figure 3.1
`
`Melting~po1'r1t—composition
`diagram for two hypothetical
`solids, A and B.
`
`mol %A 100
`mo] % B
`O
`
`___|
`0
`100
`
`melt from that of the eutectic mixture. This increases the vapor pressure of A in the
`solution according to Raoult’s law (Eq. 4.2) and raises the temperature at which solid
`A is in equilibrium with the molten solution. The relationship between the equilib-
`rium temperature and the composition of the molten solution is then represented by
`curve EP in Figure 3.1. When the temperature reachesf, no solid A will remain and
`melting of the sample will be complete. The impure sample A exhibits a melting
`“point” that extends over the relatively broad temperature range eefi Because melt-
`ing both begins and ends below the melting point of pure A, the melting point of A is
`said to be depressed.
`The foregoing analysis is easily extended to the case in which substance B con-
`tains A as an impurity. In Figure 3.1, this simply means that the composition of the
`solid mixture is to the right of point E. The temperature during the melting process
`would follow curve ED or EG, and the melting range would now be e—d or egg.
`A sample whose composition is exactly that of the eutectic mixture (point E,
`Fig. 3.1) will exhibit a sharp melting point at the eutectic temperature. This means
`a eutectic mixture can be mistaken for a pure compound, because both have a sharp
`melting point.
`From a practical standpoint, it may be very difficult to observe the initial melt-
`ing point of solid mixtures, particularly with the capillary—tube melting—point tech-
`nique used in the Experimental Procedure that follows. This is because the presence
`of only a minor amount of impurity means that only a tiny amount of liquid is
`formed in the stage of melting that occurs at the eutectic temperature. In contrast,
`the temperature at which the last of the solid melts (points at and g, Fig. 3.1) can be
`determined accurately. Consequently, a mixture containing smaller amounts of
`impurities will generally have both a higher final melting point and a narrower
`observed melting-point range than one that is less pure.
`The broadening of the melting—point range that results from introducing an
`impurity into a pure compound may be used to advantage for identifying a pure
`substance. The technique is commonly known as a mixed melting-point and is illus-
`trated by the following example. Asstune that an unknown compound X melts at
`134-135 “C, and you suspect it is either urea, I-IZNCONI-I2, or tnms—cinnam_ic acid,
`Cgl-I5CH=Cl-ICOZH, both of which melt in this range. If X is mixed intimately with
`urea and the melting point of this mixture is found to be lower than that of the pure
`
`ibi
`© 2011 Cengage Learning. All Rights Reserved. May not be scanned, Copied or duplicated, or posted to §l}§$iidl9’h%ges$)lQwel3dft(n=l.1i§ virhizdlnasglvii tr? part.
`
` Temperature(°C}m»
`
`1.
`
`.T_,_'.E_,
`E
`SolidA + Solid s
`I
`F
`'
`j
`1
`l
`l
`._|_
`30
`60
`40
`20
`20-
`40
`60
`80
`Composition
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`116
`
`Experimental Organic Chemistry I Gilbert and Martin
`
`Micro Me|ting~Puint
`Methods
`
`
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`compound and pure urea, then urea is acting as an impurity, and the compound
`cannot be urea. If the mixture melting point is identical to that of the pure compound
`and of urea, the compound is identified as urea. Obviously, this procedure is useful
`in identifying compounds oniy when authentic samples of the likely possibiiities
`are available.
`
`A convenient and rapid method for ascertaining the purity of a solid is
`measuring its melting point. A narrow melting—point range ordinarily signals that
`the sample is pure, although there is a low probability that the solid is a eutectic
`mixture. if recrystallizing a sample changes an originally broad melting range to a
`narrow one, the reasonable conclusion is that the recrystallization was successful in
`purifying the solid. Should the melting—point range remain broad after recrystal-
`lization, the sample may be contaminated with solvent and additional drying is
`required. It is also possible that the recrystallization was not completely successful
`in removing impurities, in which case .the solid should be recrystallized using the
`same solvent. If this fails to narrow the melting range satisfactorily, recrystailiza—
`tion should be performed with a different solvent.
`
`The determination of accurate melting points of organic compounds can be time-
`consuming. Fortunately, micro methods are available that are convenient, require
`negligible amounts of sample, and give meiting—point data that are satisfactory for
`most purposes. The technique using the capi1lary—tube melting—point procedure is
`the one used most commonly in the organic laboratory.
`There are practical considerations in determining melting points, and some of
`them are briefly noted here. First, the observed melting-point range, depends on
`several factors, including the quantity of sample, its state of subdivision, the rate of
`heating during the determination, and the purity and chemical characteristics of
`the sample. The first three factors can cause the observed melting—point range to
`differ from the true value because of the time lag for transfer of heat from the heat-
`ing medium to the sample and for conduction of heat within the sample. For exam-
`ple, if the sample is too large, the distribution of heat may not be uniform, and
`inaccurate melting ranges will result. A similar problem of nonuniform heat distri-
`bution is associated with using large crystals. It will be difficult to pack the sample
`tightly in the capillary melting tube, and the airspace that results causes poor con-
`duction of heat. If the rate of heating is too fast, the thermometer reading will iag
`behind the actual temperature of the heating medium and produce measurements
`that are low. The chemical characteristics of the sample may be important if the
`compound tends to decompose on melting. When this occurs, discoloration of
`the sample is usually evident, and it may be accompanied by gas evolution. The
`decomposition products constitute impurities in the sampie, and the true melting
`point is lowered as a result. The reporting of melting points for compounds that
`melt with decomposition should reflect this, as in "mp 195 °C (dec).”
`In determining the melting point of a compound, valuable time can be wasted
`Waiting for melting to occur if the proper slow rate of heating is being used on a
`sample whose melting point is unknown. It is considerably more efficient to pre~
`pare two capillary tubes containing the compound being studied and to determine
`the approximate melting point by rapidly heating one of them, and then allowing
`the heating source to cool 10-15 °C below this approximate melting point before
`obtaining an accurate melting point with the second sample.
`The accuracy of any type of temperature measurement ultimately depends on
`the quality and calibration of the thermometer. A particular thermometer may
`provide accurate readings in some temperature ranges but may be off by a degree
`or two in others. Melting points that have been determined using a calibrated
`
`SteadyMed - Exhibit 1018 - Pa e 6
`© 2011 Cengage Learning. AH Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicty accessible website, in whole or In p rt.
`
`SteadyMed - Exhibit 1018 - Page 6
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`Chapter 3 I Solids Recrystallization and Melting Points
`
`117
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`;
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`thermometer may be reported in the form ”mp 101-102 °C (corr.),” where ”corr.” is
`the abbreviation for ”corrected"; the corresponding abbreviation for values
`obtained with an uncalibrated thermometer is ”uncorr.” for "uncorrected.”
`Calibration involves the use of standard substances for the measurement of the
`
`temperature at a series of known points Within the range of the thermometer and
`the comparison of the observed readings with the true temperatures. The difference
`between the observed and the true -temperature measurement provides a correcljon
`that must be applied to the observed reading. Calibration over a range of tempera-
`tures is necessary because the error is likely to vary at different ternperatures.
`
`EXPEFHMEHNTACL PROCEDURES
`
`
`
`’ Melting Points
`
`Purpose To determine melting points using the capiliarytube method.
`
`
`
`1. If a burner is used in this experiment, be sure that no flammable solvents are
`nearby. Keep the rubber tubing leading-to the burner away from the flame.
`Turn off the burner when it is not being used.
`
`2. Some kinds of meiting~point apparatus, such as the Thiele tube, use mineral or
`silicone oils as the heat transfer medium.These oils may not be heated safely if
`they are contaminated "with even a few drops of water. Heating these oils above
`100 °C may produce splattering of hot oil as the water turns to steam. Fire can
`also result if spattered oil comes in contact with open flames. Examine your
`Thiele tube for evidence of water droplets in the oil. If there are any, either change
`the oil or exchange tubes. Give the contaminated tube to your instructor.
`
`3. Mineral oil is a mixture of high-boiling hydrocarbons and should notbe
`heated above 200 °C because of the possibility of spontaneous ignition, par-
`ticularly when a burner is used for heating. Some siliconeaoils may be heated
`to about 300 “C without danger (Sec. 2.9).
`7
`4. Be careful to avoid contact ofchemicals with your skin. Clean up any spilled
`chemicals immediately with a brush or paper towel.
`
`5.
`
`if you use a Thiele tube, handle it carefully when you are finished, because the
`tube cools slowly. To avoid burns, take care when removing it from its support.
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`l
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`' A e Calibration of Thermometer
`
`' Procedure
`(fly
`J
`
`Preparation Sign in at www.cengage.comllogin to answer Pre-Lab Exercises,
`access videos, and read the l\/lSDSs for the chemicals used or produced in this
`procedure. Read or review Sections 2.7 and 2.9.
`
`Apparatus Capillary melting—point tubes, packing tube, and melting-point apparatus.
`
`Prulncnl Carefuiiy determine the capillary melting points of a series of standard
`substances. A list of suitable standards is provided in Table 3.2. The temperatures
`
`© 201:1‘ Cengage Learning. Ail Rights Reserved. May not be scanned. copied or duplicated, or posted to a publicly accessible website, in whole or in part.
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`SteadyMed — Exhibit 1018 — Page 7