Differential Scanning Calorimetry as a General Method for Determining Purity and Heat of Fusion of High-Purity Organic Chemicals Application to 64 Compounds Candace Plato Dicision of Chemical Technology, Food and Drug Administration, Washington, D.C. 20204
DIFFERENTIAL SCANNING CALORIMETRY (DSC) has become a common technique in the last few years, and has gained wide acceptance as a valuable tool for the determination of purity. This application is based on the physical chemical equation which relates the molar concentration of total impurity present to melting point, melting point depression, and heat of fusion in the following manner: mole impurity = [AH/ RTo2]X AT X 100, where A H is the heat of fusion, R is the gas constant (1.9872 cal/mole), To is the melting point of a theoretical sample with zero impurity, and AT is the melting point depression of the sample being examined. The derivation of these values from the DSC data is described in an earlier paper ( I ) . Modifications in the earlier technique and the investigation of several solid solutions are described. Although DSC is still considered the most powerful single method for determining purity, data are presented to exemplify the types of rare problems that may be encountered, and the necessity for verification by a n independent method is illustrated. During the years since the earlier work was published, we have examined many additional compounds, and have encountered a few of the rare samples which produce misleading melting curves on the DSC. In the case of those compounds which have nonideal crystals and low heats of fusion, we have made quantitative measurements of their exceptional transition energies, and are reporting their thermal constants in addition to those determined for the normal crystals we have analyzed. For those even more unusual compounds which form solid solutions even though they have normal heats of fusion, we suggest procedures which will minimize the risk of obtaining erroneous purity values. EXPERIMENTAL
The instrument used for these determinations was the Perkin-Elmer DSC-1B. Procedure. Purities were determined using several modifications in the procedure described earlier, the most significant of which is a preliminary analysis at a sensitivity of 4 mca1,'sec full scale and a heating rate of 10 "C/min (4 X 10 "C). An unweighed sample of 1 to 3 mg is encapsulated and programmed from room temperature to beyond the melting peak. Any peaks other than the melting peak are investigated. The sharpness of the melting peak indicates relative purity, while the thermal stability of the sample is suggested by the DSC trace. Slow decomposition causes a noisy base line; rapid decomposition gives a large exotherm. We have demonstrated that the same purity value is obtained at 2 X 2.5 "C as at 1 X 0.625 "C. The slower heating rate is used when possible, but many compounds which are too unstable to tolerate analysis at 0.625 "C/min can be ( I ) C. Plato and A. R. Glasgow, Jr., ANAL.CHEM., 41, 330 (1969).
analyzed at 2.5 "C/min. In some cases, a noisy curve indicates decomposition even at 2.5 "C/min, but even though the calculated purity is somewhat inaccurate, it still provides a useful indication of what the minimum value is likely to be. Correction of AT using the temperature calibration curve that is employed to correct To is another modification. Because the To correction varies with temperature, the increments noted as degrees are not exact, but vary with temperature. The AT value is multiplied by the slope of the temperature calibration curve at that temperature. Computation of the reliability of the method was based on the heat of fusion, as it is relatively independent of sample homogeneity. None of the modifications mentioned above affect the A H measurement, so data for all chemicals with two or more A H determinations were included. Because each compound has a different A H , each deviation was normalized to its corresponding mean, and the normalized deviations were used to compute the standard deviation of the method. inThe normalized standard deviation was less than 4z, dicating very good reliability. RESULTS AND DISCUSSION
Monuron was erroneously reported in the first of these papers as being nonideal. No theoretical basis for its low heat of fusion could be deduced, so it was subsequently reexamined at a sensitivity of 4 mcalisec full scale and 10 "C/ min heating rate (4 x 10 "C). This determination clearly showed the presence of two crystal forms (170 and 175 "C); in the previous work ( I ) using the slow heating rate, the melting of only one (170 "C) was observed. The sample was converted to one form which had a normal heat of fusion (7000 cal/mole). The earlier paper also mentioned that a compound with a normal heat of fusion may form a solid solution with an impurity whose molecules are the same size and shape as those of the compound itself. Pentachloronitrobenzene (Table I, compound 20) has a normal heat of fusion; our sample was found to be in one crystal form and its purity was calculated as 99.95 mole %. A routine GLC check showed a large impurity peak which was tentatively identified as hexachlorobenzene by its retention time and the probability of its formation in the synthesis of pentachloronitrobenzene. Its molecules are essentially the same size and shape as those of the matrix compound, and it seemed reasonable to assume they could enter the crystal lattice without causing distortion. The identity and amount of contamination ( 2 7 3 were determined by comparison with a standard of hexachlorobenzene on two different G L C columns. The pentachloronitrobenzene sample was mixed with a n additional 1.3 mole hexachlorobenzene and, after melting, the mixture was allowed to solidify. DSC analysis of the mixture gave a melting curve identical to that of the original sample. This demonANALYTICAL CHEMISTRY, VOL. 44, NO. 8, JULY 1972
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Table I. Data for Purity Determination by Differential Scanning Calorimetry Purity, AH, mole cal/mole AT, “C
Organophosphates 1. O,O-Dimethyl 0-p-sulfamoylphenyl phosphorothioate, cythioate 2. O,O-Dimethyl 0-p-(dimethylsulfamoy1)phenyl phosphorothioate, famphur 3. O-(2-Chloro-4-nitrophenyl) 0,O-dimethyl phosphorothioate, dicapthon 4. 2-Chloro-1-(2,4,5-trichlorophenyl)vinyl dimethyl phosphate, Gardona Sample 1 Sample 2 5. 0-(4-Bromo-2,5-dichlorophenyl) O,O-dimethyl phosphorothioate, bromophos 6. O,O,O’,O’-Tetramethyl 0,O’-thiodi-p-phenylene phosphorothioate, Abate 7. O-2,4-Dichlorophenyl O-methyl isopropylphosphoramidothioate, Zytron 8. 0-Ethyl 0-p-nitrophenyl phenylphosphonothioate, EPN Halogenated Compounds 9. 1,2,3,4,5,6-u,e,e,e,e,e-Hexachlorocyclohexane, BHC, delta isomer Sample 1 Sample 2 10. 2,3,6-Trichlorobenzoic acid 11. Methyl tetrachloroterephthalate, Dacthal monoacid 12. Dimethyl tetrachloroterephthalate, Dacthal 13. 3-Amino-2,5-dichlorobenzoic acid, amiben 14. 2,3,5-Triiodobenzoic acid, TIBA 15. 2,4,5-Trichlorophenol 16. 2,5-Dichloro-4-methoxyphenol, hydroxy chloroneb 17. 3,5-Dibromo-4-hydroxybenzonitrile, bromoxynil 18. Methyl pentachlorophenate, PCP methyl ether 19. 2,2’-Methylenebis(3,4,6-trichlorophenol), hexachlorophene 20. Pentachloronitrobenzene, PCNB 21. Tetrachloroisophthalonitrile,Daconil 2787 22. p,p’-Dichlorobenzophenone 23. 1,l-Bis(p-chlorophenyl)-2,2,2-trichloroethanol, p,p’-Kelthane 24. Isopropyl 4,4’-dichlorobenzilate, Chloropropylate 25. Methyl bis(p-chlorophenyl) acetate, p,p’-DDA, methyl ester 26. p-Chlorophenyl 2,4,5-trichlorophenyl sulfoxide, tetrasul sulfoxide 27. 1,2,4,5,6,7,8,8-0ctachloro-3a,4,7,7a-tetrahydro-4,7-endo-methanoindane, cis-chlordane 28. 1,2,4,5,6,7,8,8-0ctachloro-3a,4,7,7a-tetrahydro-4,7-endo-methanoindane, trans-chlordane 29. 1,2,3,4,5,6,7,8,8-Nonachloro-3a,4,7,7a-tetrahydro-4,7-endo-methanoindane, cis-nonachlor 30. 1,2,3,4,5,6,7,8,8-Nonachloro-3a,4,7,7a-tetrahydro-4,7-endo-methanoindane, trans-nonachlor Chlorophenoxy compounds 31, 4-Chloro-2-methylphenoxyacetic acid 32. 2-(4-Chloro-2-methylphenoxy)propionic acid, mecoprop 33. 4-(4-Chloro-2-methylphenoxy)butyricacid, MCPB 34. 2-(2,4-Dichlorophenoxy)propionicacid, dichloroprop
strates the importance of using two entirely different methods of ascertaining purity. This same problem is common in the bridged chlorinated polycyclics. Trans-nonachlor (compound 30), when analyzed a t 4 X 10 “C, produced peaks a t 99 and 107 “C, near the melting points of cis- and trans-chlordane (compounds 27 and 28). These peak areas corresponded to 3 % of the area under the major peak a t 127 “C. Because these large, fairly round molecules might well fit into each other’s lattice positions without distortion of the crystal, a series of mixtures was examined. The temperatures of the peak maxima are presented in Table 11. Although the peaks seen for the gross mixtures were somewhat broadened, it is evident that the melting point is not lowered by increasing the amount of the second component. One sample of trans-nonachlor spiked with 3.71 mole trans-chlordane was analyzed at 1 X 0.625 1532
ANALYTICAL CHEMISTRY, VOL. 44, NO. 8, JULY 1972
To “C
99.30
6800
0.25
74.2
98.70 99.62
7000 6900
0.41 0.11
57.1 50.0
99.88 99.77
8700 8400
0.037 0.075
96.3 96.4
99.49
8100
0,14
56.3
98.34
7100
0.43
31.7
99.36 99.52
7700 7200
0.18 0.13
51.8 39.2
97.68 98.40 99.77 99.68 99.98 99.59 99.70 99.60 99.76 99.94 99.95 99.59 99.98 99.67 99.96 98.8 99.44 99.27 99.50
5300 4900 5700 7200 7300 9300 7700 5700 6500 7600 3300 8800 4400 7500 7200 5700 7500 4400 7800
1.46 1.09 0.14 0.18 0,008 0.19 0.20 0.16 0.10 0.032 0.043 0.014 0.25 0.017 0.51 0.17 0.33 0.22
137.0 137.0 129.5 177.3 158.1 201.3 230.6 68.5 88.6 190.4 107.1 165.0 144.8 253.0 146.8 75.1 72.3 38.7 142.3
99.10
6700
0.38
104.1
98.34
6800
0.68
101.1
99.93
8800
0.036
215.8
99.66
6300
0.17
127.4
99.84 99.66 99.73 99.64
7500 6900 8200 8200
0.066 0.13 0.085 0.13
119.5 93.5 100.3 116.7
0.18
Source4
“C and its purity was calculated in the usual manner. The following results were obtained : “purity,” 99.24 mole %; AH, 6900 cal/mole; AT, 0.41 “C;and mp 127.2 “C. The trans-chlordane obviously did not depress the melting point of the trans-nonachlor, nor did cis- and trans-chlordane depress each other’s. Telodrin (1,3,4,5,6,7,8,8-octachloro1,3,3a,4,7,7a-hexahydro-4,7-methanoisobenzofuran), a compound with similar structure, does, however, exhibit a normal melting point depression when spiked with cis-chlordane. Some nonideal compounds have been examined further. The molecules in a n ideal crystal acquire both translational and rotational energy as they change from solid to liquid; but these nonideal or “low heat of fusion” compounds acquire only translational energy on melting because they acquire rotational energy a t a lower temperature. These solidsolid transition temperatures and energies are presented in
Table I.
(Continued) Purity, mole
AH, cal/mole
AT. "C
To "C
99.79 99.51 99.81 99.56
6600 7000 5300 6000
0.077 0.14 0.096 0.24
77.5 42.0 98.3 130.2
98.66 99.13 99.78 99.93 99.81 99.25 99.19
8500
0.54
8500
0.35
7300 6100 6600 7100 9300
0.11 0.031 0.41 0.31
144.4 144.1 166.6 96.0 97.1 160.8 151.9
Carbamates 45. 3,4,5-Trimethylphenyl N-methylcarbamate, SD-8530 46. 4-(Methylthio)3,5-xylylmethylcarbamate,Mesurol 47. 4-Dimethylamino-rn-tolylmethylcarbamate,Matacil 48. 4-Benzothienyl N-methylcarbamate, Mobam 49. Methyl-m-hydroxycarbanilate rn-methylcarbanilate, phenmedipharn 50. S-Methyl N-[(methylcarbamoyl)oxy]thioacetimidate, methomyl
99.81 99.90 99.95 99.64 98.62 99.88
7100 7200 6400 5 200 10100 5800
0.083 0.043 0.019 0.22 0.49 0.047
120.6 121.6 95.0 129.6 150.7 78.5
Heterocyclics 51. 3-Amino-s-triazole, amitrole 52. 2-Aminobenzimidazole, 2-AB 53. 2-(4'-Thiazolyl)-benzimidazole,thiabendazole simazineb 54. 2-Chloro-4,6-bis(ethylamino)-s-triazine, 55. 2-Chloro-4(ethylamino)-6-(2-propylamino)-s-triazine, atrazineb 56. 2-Chloro-4,6-bis(isopropylamino)-s-triazine, propazineb 57. 2,4-Bis(isopropylamino)-6-(methylthio)-s-triazine,prometryne 58. N-(Trichloromethylthio)phthalimide,folpet captanb 59. N-[(Trichloromethyl)thio]-4-cyclohexene-1,2-dicarboximide,
99.85 99.62 99.83 99.81 99.44 99.88 99.33 99.95 99.79
5900 5900 8600 10500 9700 10000 6300 8500 10600
0,095 0.33 0.13 0,095 0.23 0.33 0.26 0.079
155.7 231.9 301.6 230.6 177.0 216.4 121.2 180.9 173.9
Miscellaneous 60. Methylmercuric chloride 61. Diphenylamine 62. 4,6-Dinitro-o-cresol, DNOC 63. P-Naphthoxyacetic acid 64. Succinic acid, 2,2-dimethylhydrazide, Alar
99.76 99.97 99.70 99.92 99.19
2900
0.30 0.013 0.16 0.033 0.30
173.4 326.3 86.1 156.2 152.7
Amides and ureas 35. 2-Chloro-N-isopropylacetanilide, Ramrod 36. 2-Chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide, alachlor carboxin 37. 5,6-Dihydro-2-methyl-1,4-oxathiin-3-carboxanilide, 38. 3',4'-Dichlorocyclopropanecarboxanilide, cypromid 39. Benzamidooxyacetic acid, benzadox Sample 1 Sample 2 40. N-Methyl-2,2-diphenylacetamide, desmethyl diphenamid 41. 3-(p-Bromophenyl)-l-methoxy-l-methylurea, metabromuron Maloran 42. 3-(4-Bromo-3-chlorophenyl)-l-methoxy-l-methylurea, fluometuron 43. 1,l-Dimethyl-3-(~~,~~,~-trifluoro-m-tolyl)urea, 44. 3-[p-(p-Chlorophenoxy)phenyl]-1,l-dimethylurea, chloroxuron
0.08
0.058
4400
4900 9200 9800
Sourcea
(a) American Cyanamid Co., (b) Shell Chemical Corp., (c) purified by the former Pesticide Reference Standards Section (PRSS), FDA, (d) Eli Lilly and Co., (e) Dow Chemical Co., (f) E. I. du Pont de Nemours and Co., (g) Hooker Chemical Corp., (h) Diamond Alkali Co., (i) Amchem Products, Inc., (j) International Minerals and Chemical Corp., (k) Aldrich Chemical Co., Inc., (1) Chipman Chemical Co., (m) synthesized by PRSS, FDA, (n) Givaudan Corp.. ( 0 ) John Powell and Co., (p) Eastman Chemical Products, Inc., (9) Rohm and Haas Co., (r) Geigy Agricultural Chemicals, (s) Thompson-Hayward Chemical Co., (t) Velsicol Chemical Corp., (u)Hercules Inc., (v) Monsanto Chemical Co., (w) Uniroyal, Inc., (x) Gulf Research and Development Co., (y) The Upjohn Co., (z) Ciba Agrochemical Co., (aa) Chemagro Corp., (bb) Mobil Chemical Co., (cc) Nor-Am Agricultural Products, Inc., (dd) Merck and Co., Inc., (ee) California Spray Chemical Co., (ff) K & K Laboratories, Inc., (gg) United States Rubber Co. Reported in reference I as decomposing.
Table 111, with the corresponding melting temperatures and energies. The sums of the energies of the two transitions correspond t o the heat of fusion of a "normal" crystal. The only anomolous behavior included here is that exhibited by dieldrin. Two samples produced two different sets of data. The differences were reproducible and when 1 :1 mixtures were analyzed, all four peaks could be seen in a single scan although the two melting peaks were too close t o calculate the heats of fusion separately. We assume that these were two different crystal forms, as the samples are of equivalent purity. The two are not readily inter-converted, and on several occasions thermal manipulations produced a mixture of three forms with the additional form having a solid-solid transition a t 114 "C. In one case, a 1 : 1 mixture which initially showed the pattern of four peaks reported in the table was completely converted to the two lower-melting forms by melting the mixture, cooling it a t 10 "C/min t o 47 " C ,
Table 11. Temperatures of Peak Maxima of Mixtures of a-Chlordane, 8-Chlordane, and Nonachlor Percentage of a-
Chlordane
P-
Chlordane
Nonachlor
101
100
100 100
3 5
23 46 85 25 50
Temperature of peak maximum, "C
50
97 95 73 54 15 75
99 98 97 98 98 98 98 94
107 107 107
ANALYTICAL CHEMISTRY, VQL. 44, NO. 8, JULY 1972
127 127 124 126
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Table 111. Transition Temperatures and Energies of Some Nonideal Crystals Sample Heptachlor Aldrin Heptachlor epoxide Dieldrin Sample 1 Sample 2 l:lmixofland2
- - - -
sz, sz L, s1 SZ,sz L , Temp. Temp. AH, AH, "C "C cal/mole cal/mole 83 93 5490 450 61 99 3870 330 119 166 5140 720
SI
124 130
175 180
.]:%
175
177
3850 4400 2080/ 2130
550 690 590
s1 + L,
AH,
cal/mole 5940 4200 5860 4400 5090 4800
and holding it a t that temperature. The subsequent run showed peaks a t 114, 123, 170, and 174 "C, with transition energies equivalent to those observed in the initial determination. The two resulting forms were present in approximately equal amounts. Methyl mercuric chloride (compound 60) posed several problems. Its high toxicity and volatility necessitated the use of cysteine solution traps on the exit line. MeHgCl reacts with aluminum, but the rate was unknown, so a n initial analysis was done in a sealed aluminum pan. At 100 "C, a large exotherm occurred, and material escaped from the pan. Subsequent analyses were done in gold pans, which contributed a problem of their own as they d o not seal as well as the aluminum, and a significant amount of material was sometimes lost by sublimation. However, three sets of data were obtained at 2 X 2.5 "C and the means are given in Table I. The formation of a layer of gold amalgam made the heat of fusion values questionable, even through they were selfconsistent. A check determination a t 10 "C/min, however, gave the same value, Either the film was formed after fusion, or it represented such a small part of the sample that the results were not conspicuously affected. Because there was a possibility of bromide and/or iodide contamination, we attempted to determine whether DSC could detect these contaminants, MeHgCl (calculated purity 99.8 %) was mixed
with 2.5 mole MeHgBr and melted. After solidification, the purity of the mixture was calculated as 99.3 mole Z, clearly showing that the bromide does not depress the melting point of the chloride significantly. Capillary melting points of mixtures confirm the lack of depression. A check analysis, usually GLC, is done routinely to verify the purity value obtained. The check analyses for compounds 2, 5, 6, 15,25,29, 34,42,45,46,47, 49, 52,60, and 63 of Table I have not yet been completed. The data for a number of chemicals which carried the notation "decomposes" in the first paper are now included. The samples analyzed earlier a t 0.625 "C/min did decompose, but these chemicals are not inherently thermally unstable ; purification gave samples which did not decompose o n melting, although a few still required analysis a t 2.5 "C/min. With a few exceptions, the values represent the average from three or more replicates. SUMMARY
Some minor improvements in the earlier method of purity determination by DSC have been presented: a n initial determination using a fast heating rate, the employment of a faster heating rate for unstable chemicals, and a correction in AT. The reliability of the method has been computed: the standard deviation is less than 4% in the value of the heat of fusion. This 4% would affect the purity value as 4% of the impurity measured (i.e., 99.5 0.02).
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ACKNOWLEDGMENT
The author thanks Pasquale Lombard0 for the purification and preparation of some of the samples, for consultation concerning this work, and assistance with the preparation of this manuscript. Augustus R. Glasgow, Jr., checked the calculations. The author is also grateful to the listed manufacturers who supplied most of the pure samples and much valuable information about them. RECEIVED for review January 12, 1972. Accepted March 30,1972.
Permeametry in the Knudsen-Flow Regime John F. Brock' and Clyde Orr, Jr. School of Chemical Engineering, Georgia Institute of Technology, AtLanta, Ga. LOW-PRESSURE (Knudsen region) permeametry has been investigated (1-4) on a number of occasions in recent years as a means for determining the specific surface area of fine powders. Satisfactory agreement of results with those of low temperature gas adsorption (BET) is obtained in many instances, but in other cases the permeametry results are low, Present address, Procter and Gamble Co., Cincinnati, Ohio. (1) G. Kraus and J. W. Ross, J. Plzys. Clzern., 57, 334-6 (1953). (2) B. V. Deryagin, N. N. Zakhavalva, M. V. Talaev, B. N. Parfanovich, and E. V. Makareva, "Research in Surface Forces," Consultants Bureau: New York, 1964, pp 155-60. (3) C. Orr, Jr., ANAL.CHEM., 39, 834-6 (1967). (4) N. G. Stanley-Wood, "Surface Area Measurement by a Simple
Diffusion Apparatus," Presented at the Second Particle Size Analysis Conference, Bradford, England, Sept. 1970. 1534
ANALYTICAL CHEMISTRY, VOL. 44, NO. 8,JULY 1972
sometimes very greatly so. Gas adsorption techniques are generally conceded to give as reliable a value of total surface area-/.e., external plus that of cracks, crevices, pores, and fissures, as can presently be obtained. This has led to the suggestion (3) that agreement between the two techniques results when the powders are nonporous and that permeameter values less than BET ones indicate the presence of pores. Fortunately, the area associated with pore walls can be independently evaluated by a mercury pressure-intrusion technique. If Knudsen-flow permeameter values are indeed representative of external area, these values added to mercury-intrusion areas should equal the total area and coincide with BET values. That this is so within measurement limitation for at least 16 different materials is the basis for this report.
