Dipole Attraction and Hydrogen Bond Formation in Their Relation to Solubility
`Author(s): .Toel H. Hildebrand
`
`Source: Science, New Series, Vol. 83, No. 2141 (.Tan. 10, 1936), pp. 21-24
`
`Published by: American Association for the Advancement of Science
`Stable URL: http://www.jstor.org/stable/1662176
`Accessed: 20-04-2016 19:59 UTC
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`MYLAN PHARMS. INC. EXHIBIT 1050 PAGE 1
`
`

`
`S
`
`VOL. 83
`
`SCIENCE
`
`FRIDAY, JANUARY 10, 1936
`
`N0. 2141
`
`Special Articles:
`Spectroscopic Similarity between Ergot (Lysergic
`Acid) and the Yohimbine Alkaloids.‘ DRS. M. S.
`KHARASCH, D. W. STANGER, M. A. BLOODGOOD and
`R. R. LEGAULT.
`The Ergot Alkaloids.
`The
`Structure of Lysergic Acid: DR. WALTER A. JACOBS
`and DR. LYMAN C. CRAIG.
`The Chromosomes of
`Drosophila ananassae: PROFESSOR BERWIND P.
`KAUFMANN ......................................................................................................
`Scientific Apparatus and Laboratory Methods:
`Cardboard for Anatomic Reconstruction Models:
`PROFESSOR R. M. STRONG. An Improved Thermo-
`regulator: DR. ROBERT D. STIEHLER.
`..
`Science News ....................................................................
`
`36
`
`21
`24
`
`26
`29
`
`The American Association for the Advancement of
`Science:
`Dipole Attraction and Hydrogen Bond Formation
`in Their Relation to Solubility: PROFESSOR JOEL
`H. HILDEBRAND .................................................................... ..
`Women in Science: DR. FLORENCE R. SABIN
`Scientific Events:
`the
`The Biochemical Research Foundation of
`Franklin Institute; Awards of the American So-
`ciety of Civil Engineers; The Award of the Wil-
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`
`32
`
`35
`
`DIPOLE ATTRACTION AND HYDROGEN BOND
`FORMATION IN THEIR RELATION TO
`SOLUBILITY"
`
`By Professor JOEL H. HILDEBRAND
`UNIVERSITY or OALIEORNIA
`
`THE germ of the idea of a hydrogen bond may be I
`seen in some of the formulas of Werner involving
`covalent linkage; however, he avoided committing him-
`self concerning the nature of this linkage, which was
`little more than a dotted line, and very different from
`its modern significance of a definite electron pair
`bond. Moore and Winmil1,1 in 1912, wrote for-
`mulas containing light and heavy lines to account
`for the weakness of trimethyl amine in aqueous solu-
`tion,
`(CH3)3—=_N—H—OH, as compared with tetra-
`methyl ammonium hydroxide, (CH3), 2 N—OH. The
`former may be interpreted as the first definite repre-
`*Address of the vice-president and chairman of the
`Section of Chemistry, American Association for the Ad-
`vancement of Science, St. Louis, December, 1935.
`1T. S. Moore and T. F. Winmill, Jour. Chem. Soc.,
`London, 101: 1675, 1921.
`.
`
`In the following year
`sentation of a hydrogen band.
`Pfeifferz suggested as an explanation of the weakness "
`of O-hydroxyanthraquinone that the hydrogen atom is
`“coordinately” bound to the oxygen atom of the adja-
`cent carbonyl group. The first recognition "of
`the
`hydrogen bond as a general phenomenon we owe to
`Latimer and Rodebush.3 They called attention to the
`effects of hydrogen bond formation, Such as the high
`dielectric constant of water,‘ which ordinary dipoles
`do not show. Lewis4 cited the existence of HF,“ but
`not F2“ as offering direct evidence of a hydrogen
`bond. The unusual properties of ammonia, water
`
`2 P. Pfeiffer, Ann., 398: 137, 1913.
`3 W. M. Latimer and W. H. Rodebush, Jour. Am. Chem.
`Soc., 42: 1419, 1920.
`-
`4 G. N. Lewis; “Valence,” p. 109,‘Cheniical Catalog
`Company, 1923.
`
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`MYLAN PHARMS. INC. EXHIBIT 1050 PAGE 2
`
`

`
`'22
`
`SCIENCE
`
`Von. 83, No. 2141
`
`and hydrogen fluoride have come to be regarded
`largely as the effects of their hydrogen bonds. The
`lattice structure ‘currently attributed to ice and to
`water assumes the hydrogen atoms to be placed on
`lines joining pairs of oxygen atoms,5 and similar evi-
`dence exists for methanol.“ The extraordinary stabil-
`ity of double molecules of acetic acid and of, appar-
`ently, six-fold polymers of hydrogen fluoride in the
`gaseous state7 presents evidence of the strength which
`such bonds may assume. Kumlerg has pointed out
`abnormalities in polarization which accompany hydro-
`gen bond formation. The writer, in his studies of
`solubility, has discovered a number of solutions whose
`behavior is highly anomalous if the explanations are
`based upon dipole moment alone, but which become
`quite “reasonable” if account
`is taken of hydrogen
`bonds. The purpose of this paper is to present a
`few of the most striking of these cases.
`Table 1 gives the solubilities of several organic
`liquids in water, together with their dipole moments.
`(The data quoted in this paper are available, except
`as noted, in the International Critical Tables.) The
`first four liquids, benzene, nitrobenzene, aniline and
`
`phenol, become rapidly more soluble in water in the
`order named. If ordinary “polarity” were responsible
`TABLE 1
`SOLUBILITY or Lroums IN WATER, 20°
`
`.
`. . . . . . . .
`. . .
`. . . . .
`Benzene
`. . . . . . .
`. . . . .
`Nitrobenzene .
`. . . . . . .
`. . .
`.
`.
`Aniline .
`. .
`.
`. .
`Phenol
`. .
`.
`.
`.
`. . .
`. . . . .
`.
`. . . .
`
`.
`. .
`. . . .
`. . . . .
`. .
`. . . .
`.
`. .
`. . . .
`.
`. .
`
`Per cent.
`0.06
`0.19
`3.49
`8.2
`
`u. x 1013
`0.
`4.19
`1.51
`1.70
`
`.
`
`. . .
`.
`. . . . . . . . . .
`. .
`.
`.
`Ethyl iodide . .
`. . .
`.
`.
`. . . . .
`. .
`. . .
`. . . .
`Ethyl alcohol
`.
`. . .
`Propyl chloride .
`.
`.
`. .
`. . .
`. . .
`. . . .
`. . .
`Propyl iodide .
`. .
`. . .
`.
`.
`. . . .
`.
`. . . .
`Propyl alcohol
`. . . . .
`. .
`. .
`. . . . . .
`. . . .
`Water
`. .
`. .
`.
`.
`. . .
`. .
`. . . .
`. . .
`. . .
`.
`.
`. . .
`
`0.40
`oo
`0.27
`0.11
`oo
`
`1 66
`1 70
`2.0
`1.6
`1 7
`1.85
`
`‘
`
`We should expect to find nitrobenzene, with by far the
`highest dipole moment as well as the highest dielectric
`constant, to be the most soluble in water; however, this
`1 is far from being the case, for it is only three times
`as soluble as the non-polar benzene, whereas phenol,
`with a much smaller moment, is 137 times as soluble.
`The molecular fields of the non-polar portion of these
`four molecular species must be nearly identical so that
`hydrogen bond formation appears to offer the only
`explanation. This is stronger in water than in am-
`monia, as shown, for example, by their boiling points,
`and we should expect phenol to associate with water
`
`5 J. D. Bernal and R. H. Fowler, Jour. Chem. Pkg/8., 1:
`515, 1933. S. Katzoff, Jam‘. Chem. Phys, 2: 841, 1934.
`6 Warren, Phys. 1361)., 44: 969, 1933.
`7 J. Simons and J. H. Hildebrand, Jom. Am. Chem. 1800.,
`46: 2133, 1924..
`8 w. D. Kumler, ma, 57: 600, 1935.‘
`
`in this way more strongly than does aniline, as is
`indeed the case.
`
`The ethyl and propyl halides and alcohols given
`Table 1 differ but little from each other in their dipole
`moments, hénce, if their solubilities in water were due
`simply to electrostatic dipole attractions their solubili-
`ties should be of the same order of magnitude. Propyl
`chloride and iodide have solubilities paralleling their
`dipole moments, but
`the alcohols, which can form
`hydrogen bonds with the water, mix with it
`in all
`proportions.
`,
`Table 2 gives the per cent. deviation of the total
`vapor pressure curves of carbon disulfide solutions
`from Raoult’s law. The first three liquids show devi-
`ations such as might be expected from their dipole
`moments, but methyl alcohol, with a much smaller
`moment than acetone, shows a much larger deviation,
`due, we may assume, to the hydrogen bonds in the
`alcohol which have the effect of enhancing the inter-
`molecular forces and resisting penetration by the non-
`polar carbon disulfide.
`
`TABLE 2
`PER CENT. DEVIATION or TOTAL VAPOR PRESSURE CURVE
`FROM RAoULT’s LAW.
`20°
`
`Dipole moment
`Carbon disulfide
`p. x 10“ e.s.u.
`with
`. . .
`1.1
`Ethyl ether . . . . . . . .
`Chloroform . . . . . . . . . . .
`1.1 .
`Acetone . . .
`. . .
`.
`. . . . . . .
`2.8
`Methyl alcohol
`.
`. . . . .
`. .
`1.7
`
`Per cent.
`deviation
`17
`15
`59
`>70 (2 liq.)
`
`Table 3 gives solubilities in eight liquids of the non-
`polar gases hydrogen and nitrogen, and the polar,
`hydrogen-bond forming ammonia. We see again here
`that dipole moment alone is of little significance.
`Ether, in spite of its moment of 1.14, is a better solvent
`for the non-polar gases than benzene. The ether
`dipole is sufficiently buried to do little more than
`enhance the molecular field, but not enough to “squeeze
`out” the non-polar solute. Aniline, although much
`less polar than nitrobenzene, is a poorer solvent, be-
`cause, we believe, it “associates” with itself through
`the hydrogen bond. The increase in such association
`as we proceed through ethanol and methanol to water
`sharply reduces the solvent power. With ammonia
`as solute, the order is the reverse, since ammonia is
`TABLE 3
`SOLUBILITY on GASES. MOL PER CENT.
`
`. . .
`.
`.
`.
`.
`.
`Ether
`. . . .
`.
`.
`Toluene .
`. .
`.
`.
`.
`.
`Benzene
`Nitrobenzene .
`.
`Aniline .
`. . . .
`.
`.
`Ethanol
`.
`. . .
`.
`.
`Methanol
`.
`.
`. . .
`Water
`.
`.
`. . . .
`.
`
`.
`
`p. x 1013
`e.s.u.
`
`1.14
`0.4
`0.
`4.08
`1.51
`1.70
`1.68
`1.85
`
`H2
`20°
`
`0.061
`0.037
`0.025
`0.015
`0.012
`0.021
`0.015
`0.0015
`
`N2
`20°
`
`0.124
`0.053
`0.043
`0.026
`0.011
`0.033
`0.022
`0.0013
`
`NHa
`0°
`
`7.9
`0.26
`. . .
`.
`.
`39.
`43.9
`48.
`
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`MYLAN PHARMS. INC. EXHIBIT 1050 PAGE 3
`
`

`
`JANUARY 10, 1936 '
`
`SCIENCE
`
`‘
`
`23
`
`able to form these bonds very strongly and thus pene-
`trate the “associated” water molecules.
`
`Fig. 1 shows a plot of the logarithm of the solubility
`
`0
`
`MP2? of Naph ha/ene
`
`\\
`
`\
`
`Benzoic acid
`
`—o./
`
`‘ \
`
`1
`
`—-
`
`Idea/—~.————»——-—
`
`N/‘frobenzene
`
`\\
`\
`
`\
`
`Ace;f/"c
`acid
`
`‘
`
`\
`
`.
`
`Bufang Hexane
`
`-‘_~
`
`Acetone
`
`' \
`
`30
`
`3/
`
`29
`
`_
`
`0'2
`
`2‘
`3’
`
`~03
`
`'0.4
`
`-0.5
`
`v 28
`
`/0“/r
`FIG. 1. Freezing point lowering of naphthalene caused
`by various liquids.
`
`of naphthalene, expressed as mol fraction, in a selected
`list of solvents.
`It may be regarded as expressing
`the “freezing point lowering” of naphthalene. This
`substance has zero moment but it nevertheless forms
`
`nearly ideal solutions with nitrobenzene in spite of the
`Both have molecular fields
`' high moment of the latter.
`about equally enhanced over that of benzene, so that
`their behavior indicates that the nitrobenzene molecules
`
`‘Ace-
`show but little electrostatic dipole association.
`tone with a smaller moment shows, nevertheless, a
`larger deviation on account of a weaker molecular
`field. Hexane, with a still weaker field, deviates still
`more, but the difference in field strengths, substituted
`in the approximation formula for solubility,9 repro-
`duced the solubility almost exactly, giving the smooth
`curve running through the points. Acetic acid ap-
`pears to form definite dimers, doubtless through two
`hydrogen bonds, accordingly, its curve in dilute solu-
`tions—concentrated in naphthalene, approaches the
`dotted curve drawn on the assumption of complete
`formation of a dimer which obeys Raoult’s law.
`Its
`9.1. H. Hildebrand and S. E. Wood, J. Chem. Phys.,‘
`1: 817, 1933; J. H. Hildebrand, J. Am. Chem. Soc., 57:
`866, 1935.
`'
`
`deviation lower down accords with the difference in
`
`field strength of the hydrocarbon portions of the two
`species. Benzoic acid, as might be expected, forms a
`weaker dimer with field strength nearer to that of
`naphthalene. Butanol associates through the forma-
`tion of hydrogen bonds, but it forms less definite
`polymers than the acids, and these break down more
`readily as they are diluted with naphthalene. The
`striking fact to note here is the enormous difference
`between butanol and acetone. The former not only
`has a larger hydrocarbon portion to the molecule but
`a much lower dipole moment, both of which should,
`operating alone, make it a better solvent for naphtha-
`lene. That the contrary is the case seems to admit
`of no other explanation than that the strength of its
`hydrogen bonds renders it inhospitable to naphthalene.
`The difference between association due to hydrogen
`bonds and that due simply to dipole attraction is
`strikingly illustrated by Fig. 2, giving variations in
`
`
`
`
` Polarizationofpolarcomponem‘
`
`Mole fraction of polar componenl
`
`FIG. 2. Variation of molar polarization with concen-
`tration.
`
`molar polarization with concentration in solutions with
`non-polar components.”
`It is evident that the alco-
`
`10 Data from J. Krchma and J. W. Williams, Jam‘. Am.
`Chem. Soo., 49: 1676, 2408, 1927; C. P. Smyth and W. N.
`Stoops, ibid., 42: 1419, 1920. An excellent discussion of
`association is given by C. P. Smyth, “Dielectric Constant
`and Molecular Structure,” Chemical Catalog Company,
`New York, 1931, Chap. IX.
`0]‘. also 0. Hennings, Z.
`phystlo. G'hem., B 28: 267, 1935.
`-
`
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`
`MYLAN PHARMS. INC. EXHIBIT 1050 PAGE 4
`
`

`
`24
`
`‘
`
`e
`
`SCIENCE
`
`VOL. 83, No. 2141
`
`hols represent a class Very different from the other
`liquids, acetone, chlorobenzene and ether.
`(Nitrobe__n-
`zene shows a curve similar to that of acetone but much
`steeper.) Any simple treatment based upon dipole
`attraction that might apply to the latter group would
`obviously not apply to the former.
`Indeed the enthu-
`siasm with which dipole moments have been applied
`to all such problems should be strongly tempered by
`a realization of their inadequacy to deal with, first,
`molecules associated through hydrogen bonds, second,
`molecules of zero moment but containing vectorially
`opposed polar groups,“ and, third, the intermolecular
`forces to the neglect of van der Waals forces.
`So far
`
`as this last is concerned, London” has calculated the
`magnitude of the components of the potential between
`molecules of H01 and of HBr. These components
`
`the van der VVaals potential due to the
`are, first,
`“dispersion effect,” or interaction of the electron sys-
`tems, second, the interaction potential of the perma-
`nent dipoles,
`third,
`the interaction of the moments
`induced in each by the permanent dipole of the other.
`The potentials due to the indiiced moments are nearly
`negligible compared to the others. By far the largest
`component is the “dispersion effect.” Although the
`dipole moment of H01 is 1.03 x 1043 e.s.uL, the poten-
`tial due thereto is only about one fourth of the disper»
`sion potential, and with I-IBr, with a moment of
`0.78><l0—18, the dipole potential is only about seven
`per cent. of the dispersion effect.
`It should be evident
`from this that all attempts to deal with the interaction,
`of polar molecules on the -basis of their dipole forces
`alone are doomed to failure.
`’
`
`WOMEN IN SCIENCE‘
`By Dr. FLORENCE R. SABIN
`THE ROCKEFELLER INSTITUTE FOR MEDICAL [RESEARCH
`
`President Park: I can not express adequately to you
`and to your committee the pleasure I feel in receiving
`this prize, for there is distinction to an honor which
`bears the name of M. Carey Thomas.
`I confess at once that any award forwork in science
`must awake a certain sense oftimidity; for onecan
`never be sure that research will stand. How often
`
`have the supposed facts and theories of the very ablest
`been reversed by new evidence!
`In the case of my
`own work, I can see with great clarity how far it is
`from reaching its goal.
`.
`1
`But why does an honor from Bryn Mawr touch so
`deep a sense of gratification”!
`It is because of the
`traditions of this placeland all that they have meant
`for scholarship and for women.
`I
`remember
`so
`vividly getting the essential quality of this spirit on
`the occasion, now thirteen years ago, when Miss
`Thomas retired fromvthe presidency of the college.
`There was not a person who spoke at that time, former
`members of the faculty and former students alike, who
`did not bring out that the influence of Miss Thomas
`had been in a quite unique manner toward fostering‘
`high standards of work. This is what she has be-
`queathed to the college. What a gratification it must
`be to her, President Park, that you have the same
`feeling for scholarship and that you have carried on
`and extended the high traditions of Bryn Mawr.
`It seems to me fitting that I should speak of certain
`
`11 J. H. Hildebrand and J. M. Carter, Proc. Nat. Acad.
`Sczl, 16; 285, 1930.
`12 F. London, Z. Phystk, 63: 245, 1930.
`1 Response on receiving the M. Carey Thomas Prize on
`the occasion of the fiftieth anniversary of the founding of
`Bryn Mawr College.
`
`points concerning the influence of Miss Thomas on
`education in science. As is well known, the greatest
`function of the president of any institution of learn-
`ing _is
`the choosing of a faculty. Moreover,
`real
`ability for this function consists in having the insight
`to select scholars while they are still young, before
`they have demonstrated their full power. To use only
`one example, but that one striking enough, the early
`faculty of Bryn Mawr College included three young
`men who became our most distinguished biologists."
`Edmund B. Vvilson, Thomas Hunt Morgan and
`Jacques Loeb have given American biology_world-
`preeminence.
`It was, I think, Professor ‘Wilson who
`first won from Europe full recognition for American
`biological research.
`In 1911 he was invited by the
`editor of the Archie fin’ mih-roskopische Anatomic to
`republish in a foreign journal his work on the X—chro-
`mosome in relation to sex.
`It is interesting to recall
`that in this article he gave full credit to the work of
`Netty Stevens, who had independently and at the same
`time made the same discovery. As you well know, Miss
`Stevens did her work here and she had here a research
`
`position with almost no obligations for teaching, such
`as is seldom held in our universities except by the
`professor emeritus. Such a group of scientists as was
`and is still assembled here depends, of course, on the
`presence of the graduate school which was established
`at Bryn Mawr from the start along with the under-
`graduate department.
`I want next to dwell on the influence which Miss
`Thomas exerted on medical education. The opening
`of the Johns Hopkins Medical School
`in 1893 was
`made possible by a fund raised by a group of women
`
`’
`
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`MYLAN PHARMS. INC. EXHIBIT 1050 PAGE 5