Hydroxylammonium Acetate as Carbonyl Reagent TAKERU HlGUCHl and C. H. BARNSTEIN School of Pharmacy, University of Wisconsin, Madison 6, W i s .
.4n analytical method for carbonyl determination based on oximation with hydroxylammonium acetate in acetic acid is shown to be superior in many respects to those methods already proposed. The results of the present investigation indicate that the oximes formed are sufficiently weaker as bases to permit satisfactory titration of the reagent in acetic acid with perchloric acid. Oximes of aliphatic and cyclic ketones, furthermore, often possess such intermediate basic strength as to permit their direct titration in acetic acid in the presence of excess reagent. Unlike many other carbonyl methods proposed, the present method is unaffected by large concentrations of organic acids of w-idely differing strength. This study includes a method for preparing hydroxylammonium acetate, the chemical kinetics of its reaction with a typical ketone, and the kinetics of its breakdown in acetic acid.
A
LTHOUGH considerable progress has been made recently in the field of organic functional group analysis, the problem of determining aldehydes and ketones, especially in the presence of organic acids, has not yet been solved satisfactorily. The results of an exploratory study made on the use of hydroxylammonium acetate in acetic acid as a reagent for this purpose are presented here. Classically, the preferred methods of carbonyl determination have been based on the oximation reaction with hydroxylamine hydrochloride as the reagent:
R
R
\
c=O
/
R
+ H2?OH I
H
-
C1
\
C=NOH
+
/
+ H2O + HCl
number of procedures for electronietric estimation of the acid liberated in Reaction 1. Eitel ( 2 ) proposed a method of oximation in aqueous solution followed by filtration of the insoluble oxime and subsequent titration of the filtrate to p H 4.1 with standard alkali. I n another report, Smith and Mitchell (Y),in order to permit carbonyl determination in the presence of carboxylic acids, adjusted an alcoholic solution of hydroxylamine hydrochloride to p H 2 50; after oximation with this reagent, the solution was titrated potentiometrically to p H 2.50 with standard alkali. I n both methods the end points are not totally satisfactory. Although free hydroxylamine is known to be unstable, potentiometric methods which employ either partially or totally neutralized hydroxylamine hydrochloi ide have been used. Knight and Swern (4), who used alcoholic hydroxylamine hydrochloride half neutralized with sodium hydrouide, found that the reagent decomposed with a half life of approximately 13 days a t 26" C. The chief drawback to this method, therefore, lies in the fact that a relatively unstable reagent is heated to reflux with the carbonyl compound, a factor which makes analytical control between the blank and the reagent very difficult because breakdowr of the reagent may be expected to be accelerated considerably a t the boiling temperature of the solution.
(1)
R
The method of Bryant and Smith (I), for example, carries out this reaction in an alcohol-pyridine solution. The pyridine hydrochloride produced b y the reaction is titrated by them with a standard alcoholic solution of sodium hydroxide, using bromophenol blue as the indicator. The end point of the titration is taken as that a t which the color of the indicator matches that of a blank solution. An accurate identification is extremely difficult however, because the color transition is uniformly very gradual throughout the titration. Similarly, potentiometric titration of the solution reveals an equally poorly defined end point, as shown in Figure 1. It is evident that no clear indication is available as to where the equivalence point of the titration lies, because the typical sigmoid shape is almost entirely absent. Such an uncertain end point may be anticipated on the basis of the nature of the acidic components present. Any attempt to differentiate between pyridine hydrochloride and hydroxylamine hydrochloride by titration of the former with standard alkali in the presence of an excess of the reagent n-ould lead to considerable difficulty. I n water, at 25" C., pyridine ( k b = 2.3 X and hydroxylamine (kb = 1.1 X have nearly the same basic strength. Although the numerical values cited are not absolutely valid for alcoholic solutions, they are sufficiently representative of their relative basic strength to indicate the difficulty of the problem. There are, in addition to the method of Bryant and Smith, a
"F
1100
1050
I I I I I I I I I I I 0
1
2
3
MII.LIL1TERS
4
5
6
7
8
9 1 0
O F 0 5 N SODIUM HYDROXIDE
Figure 1. Potentiometric titration curve for oximation of acetone bjmethod of Bryant and Smith ( I )
It would thus seem that a modification of the present oximation methods is highly desirable which (1) would yield a sharper titrimetric end point, (2) would not be subject to interferences from organic acids, and (3) would not depend for its accuracy on a highly unstable reagent. Because weak amines generally can be determined more accurately in less basic solvent systems than water, some improvement in the end point may be expected in acidic solvents such as acetic acid. The extent to which Reaction 1 will go to completion, moreover, may be favored by a nonaqueous acidic system because of the low concentration of mater 1022
1023
V O L U M E 2 8 , N O . 6, J U N E 1 9 5 6 and because i t furnishes a favorable environment for the oxime, which displays somewhat basic tendencies. For these reasons, the feasibility of determining carbonyl groups by oximation in acetic acid was studied. POTEhTIOMETRIC TITRATIONS OF fIYDROXYLAMMONIUJ1 ACETATE AND OXLMES IN ACETIC ACID
Hydroxylamine, ahich exists essentially as hydroxylammonium acetate in acetic acid, can be readily determined by potentiometric titration with perchloric acid. The sharp break obtnined during such titrations is illustrated by curve B in Figure 2.
cases in which a t least one of the substituents is either an aromatic group or hydrogen, the oxime appears to be nontitrable. The relative basicity of nitrogen compounds is generally attributed to the extent to which the unshared electron pair of the nitrogen is made available to coordinate with the proton of an acid. An aromatic group conjugated with the oxime, however, displays an electron-withdrawing effect, with the result t h a t the oxime hydrogen is more loosely held and the basic strength is consequently less than normal. Alkyl groups, on the other hand, appear to enhance the basicity of the oxime nitrogen through an inductive effect. KINETICS OF OXIMATION IN ACETIC ACID
Chemically, the oximation reaction apparently involves an attack on the carbonyl carbon by hydroxylammonium acetate as the slow, rate-determining stage. I t can be assumed, therefore, that the reaction proceeds more slowly as the substituent groups of the carbonyl compound become more complex, because the carbonyl carbon is sterically shielded from the approaching nucleophilic reagent. I n practice this is found to he true; cyclic and phenyl ketones react much more slowly with hydroxylammonium acetate than do aliphatic ketones, while aldehydes seem to react Tithin a matter of minutes. I n general, ketones (particularly complex ketones) would be expected to react much more slowly than the corresponding aldehydes, and reaction time should be extended for completion of oximation.
7c3
650
600
E,
550
0
?
:500 J
450
650
600 MILLILITERS OF 0 1 5 N PERCHLORIC A C I D
Figure 2. Potentiometric titration of hydroxylanimonium acetate A.
B.
2
550
0
?
Following oximation of benzaldehyde in acetic acid In blank solution of acetic acid
i
500
450
Addition of a carbonyl compound to such a system prior to titration results in the reaction 400
R \
C=O
/
R
+
R
\
+
HINOH
I
H
C=NOH
-+
/
+
H,O
+
H + (2)
150
R
with the production of a hydrogen ion which in turn neutralizes an equivalent of acetate ion. This behavior is evident in curve A of Figure 2, which is a potentiometric titration curve of hydroxylammonium acetate solution following the addition of a weighed amount of benzaldehyde. The difference in the volume of perchloric acid solution at the two end points corresponds closely to the amount of benzaldehyde added. I t is evident, moreover, from these curves, that end point detection in this system is considerably superior to that possible in alcohol or pyridine. Because of the nature of the solvent, the oxime formed may under certain circumstances behave as a base. This is illustrated in a titration follon-ing the oximation of methyl ethyl krtone as shown in Figure 3. The difference between the final and initial breaks corresponds to the amount of acid reacting with the oxime formed in the reaction. The basicity of the oxime seems to be a function of the substituent radicals (R) of the carbonyl group. For all compounds in which both are alkyl substituents the oxime seems to be sufficiently hasic to permit titration with perchloric arid. I n those
Z MILLILITERS OF O l S N
PERCHLORIC A C I D
Figure 3. Potentiometric titration of hydroxylammonium acetate and methyl ethyl ketoxime following oximation of methyl ethyl ketone in acetic acid
Kinetically, oximation would be expected to be a second-order reaction, the rate of reaction being effectively proportional to the concentration of both reactants. d [oxime] Rate = -= k [carbonyl] [hydroxylammonium acetate] dt
(3)
The rate of such a reaction may be increased readily by increasing the concentrations of the reactants-e.g., doubling the concentrations of both reactants should cause the reaction rate to increase by a factor of nearly 4. Complex ketones, which react completely only after 1 to several days in dilute solution, react within a few hours in solutions of sufficiently high concentration. Bldehydes, on the other hand, appear to react rapidly in both concentrated and dilute solutions. The general proce-
1024
ANALYTICAL CHEMISTRY
dure thus should include reaction in highly concentrated solution, followed by dilution, if necessary, with acetic acid, and titration with perchloric acid. T o determine the order of magnitude of the oximation rate in acetic acid, a kinetic study was made of the reaction between acetophenone, a slow reacting ketone, and hydroxylammonium acetate. I n Figure 4 the data thus obtained are graphed t o show the second order nature of the reaction. For these runs the initial concentration of both reactants >\as 0.5Jf.
Kinetics of Degradation of the Reagent. Although it is stable as the dry salt, hydroxylammonium acetate undergoes decomposition a t a slow but measurable rate in acetic acid solution. Figure 5 is a first-order plot of the data obtained as a result of degradation of hydroxylamnionium acetate in 0.LW solution in acetic acid a t temperatures of SO", 60", and 80" C. Corresponding rate constants were obtained from the relationship: k = - slope X 2.303
(4)
The rate constants a t several temperatures and the calculated heat of activation for the reaction are shown in Table 11. Also included in the table are extrapolated data a t 25" C. and the half lives of tIyo stock solutions of the acetate kept a t room temperature. Despite some expected seasonal variations, the latter values appear to be in excellent agreement 11-ith the projected a n w e r . There seems to be very little doubt that the mechanism of degradat,ion is essentially the same a t room temperature as a t the elevated temperatures. Despite the thermal labilit,y of hydroxJ-lammonium salts in solution, a number of earlier methods published have advocated reflux or other higher temperature conditions to accelerate the oximation step. The data obtained here show that considerable caution should be exercised before such procedures are adopted. T I M E IN M I N U T E S
Figure 4.
Rate of oximation of acetophenone in 0.5M solution in acetic acid Plotted as second-order reaction
Table I. Comparison of Rates of Oximation of Acetophenone in iicetic Acid and in Methanol-Pyridine Temperature,
c.
I n Table I the rate constants calculated from Figure 4 are tahulated, along n ith those nhich were determined for oximation of the same compound in methanol-pyridine solution by Suratt, Proffitt, and Lester (8). Comparison shons that, under equivalent conditions, the reaction proceeds a t a noticeably less favorable rate in acetic acid solution than in the more basic solvent HoFever, this is not a serious dravback because the reaction velocity in acetic acid is still sufficiently great to permit convenient determination of nearly all carbonyl compounds even at room temperature. Thus, oximation in acetic acid of a 0.5.11 solution of acetophenone, an especially slov reaction, goes to better than 99% completion in 2 hours in the presence of 1 N hydroxylammoniurn acetate. From all indications, the o\imation reaction goes essentially to completion. The reverse reaction-Le., the formation of hydroxylammonium salts from the oxime-appears to be negligible, even in the presence of traces of water and excess of perchloric acid. CHEMISTRY AND STABILITY O F HYDROXYL4M\.IONIUM ACET4TE
Preparation of Hydroxylammonium Acetate. Because there was no available source of the reagent, hydroxylammonium acetate for the study of oximation was prepared as follow A mixture of hydroxylamine hydrochloride in absolute ethyl alcohol vias cooled in an ice miter bath, and to it was added a few drops of phenolphthalein (1% in ethyl alcohol). Free hydroxylamine was liberated by s l o d y adding to this mixture a saturated solution of sodium hydroxide in absolute ethyl alcohol, with alternate agitation and cooling. Hydroxylamine decomposes rapidly in alkaline solution; therefore, it TYas important that an excess of base was not present. $Then all the hydroxylamine appeared to be liberated from the salt, the mixture x a s filtered directly into an excess of glacial acetic acid. Excess alcohol and acid were removed from the filtrate by distillation under reduced ressure until there remained about one fourth of the originaf volume. T o this was added sufficient anhydrous ether t o precipitate the hydroxyl ammonium acetate, which was separated by filtration. The precipitate was washed with a little ether and dried at room temperature.
25 30 35
Rate Constant, k X lo3 Liter/>Iole/SecondllethanolAcetic acid p j ridinea 1.01 1.57 2.12
40
24 6 Zf 9 48
a
Data of Suratt, Proffitt, and Lester (8)
I t was found experimentally that neither strong acid nor strong base influenced the rate of decomposition of hydroxylamnionium acetate in acetic acid. The kinetic data sho\v that hydroxylammonium acetate in acetic acid is much more stable than neutral hydroxylamine in water, a factor Xvhich is strongly in favor of its use as an oxiniating reagent. It is sufficiently stable a t room teniperature so that its decomposition may be disregarded entirely. even for reactions of several hours' duration. Hos-ever. its stability decreases rapidly n-ith rising temperature, and heating of solutions should be avoided, particularly if comparison with B blank is necessary. For those ketones which yield relatively strongly basic ketoximes, on the other hand, a blank titration is not necessary, and careful heating is not believed to be objectionable. The temperature coefficient of the breakdon-n of the reagent is roughly trike that of the oximation reaction, a factor which should be considered before attempting to s:ieed up the analysis by raising the temperature of the system. Although decomposition products of hydrosylamnionium acetate in acetic acid solution have not been isolated or identified, it has been denionstrated that ammonia or any other basic product is not among them. This \vas determined by refluxing an assayed solution of hydroxylammonium acetate in acetic acid for 30 minutes, after which basicity was nearly totally destroyed. Solutions of ammonium acetate in acetic acid, on the other hand, retained virtually the same titer when refluxed for 1 hour. Evidence has been cited by Perret ( 5 ) to support a proposed oxidative mechanism for the decomposition of neutral hydroxylamine in aqueous solution, whereby it is believed to be oxidized by atmospheric oxygen to the unstable dihydroxyhydrazine, xhich in turn breaks down to nitrogen and water.
V O L U M E 2 8 , NO. 6, J U N E 1 9 5 6
1025
Influence of Acetic Anhydride on Reagent. Acid-base titrations carried out in nonaqueous media generally yield substantially accentuated end points when an excess of acetic anhydride is added to the system (3). Hydroxylammonium acetate, however, reacts almost instantaneously n i t h acetic anhydride to yield the essentially neutral acylated product, S,Odiacetylh~~lrosqlamine (6).
0
Table 11.
Rate of Decomposition of Hydroxylanimonium Acetate in Acetic Acid
Temperature, C. 80 60
Half Life, Hours
R a t e Constant, Hour-' 0.160
4.5
o o m
34
92
0 00764 0 000388n 0 000011~
1785 (741/2 days)a 7 years0
Room temperature: Late winter (74 days) Early summer ( 6 2 days) Calculated AHnot = 22,800 calories/mole ' Half life and rate a t 25' and O o C . were extrapolated from experimental results obtained a t higher temperatures.
CH3C-XH-O-C-CHa
+ H10 + H +
Table 111. Quantitative Analysis of Carbonyl Compounds by Oximation in Acetic Acid at Room Temperature
(5)
Because of this interaction, care must be exercised to avoid using an>- reagents which contain excess acetic anhydride. A carefully calculated amount of acetic anhydride, sufficient to react Tvith 95 to 98Yc of the water present in reagent perchloric acid solution, \vas employed in the preparation of standard solutions of the acid. Other than that, however, glacial acetic acid solutions for osiination should he prepared Tvithout the inclusion of the anhydride.
Oximation Time N o . of Carbonyl (20-30 Min. Except DeterminaCompound Where Noted) tions Acetonea 3 Aoetonedicarboxylic acid b 3 Acetophenone a c 3 2 hours .Inisaldehyde 2 Benzaldehydea 6 6 p-Hydroxybenzaldehyde b Benzil b c . d 4 24 hours n-ButVraldeh\.de 0. 4 9 4 hours
T o determine the feasibility of the general method just described for the quantitative determination of the carbonyl function in a variety of compounds, analyses were carried out on aldehydes, ketones, keto-acids: and the like. The following procedure K:LS used for these determinations. An accuratply measured 10-ml. aliquot of O.5M hydroxylammonium acetate solution (in acetic acid) was transferred to a 100-ml. volumetric flask, and to it \vas added an amount of carbonyl compound calculated t o react with half of the reagent. After completion of osimation (20 minutes a t room temperature n-:is sufficient for aldehydes and simple aliphatic ketones) the solution wiis diluted to exactly 100 nil. n-ith acetic acid, and a 5-ml. aliquot \vas removed and titrated potentiometrically n i t h
'70
9 9 3 1 0 6 99 9 1 0 1 9 9 7 1 0 4 9 7 5 f 0 3 99 6 1 0 6 97 9 1 1 . 3 9 7 6 1 0 3 9 9 3 1 0 6 97 6 1 1 8 9 7 4 1 0 6
2
24 hours
1 2 5
HYDROXY L.A>lhIONIURI ACETATE REAGENT FOR QUAKTITATIVE AXALYSIS OF CARBONYL COMPOUKDS
Found,
2 3 a b e d
97 6
99 2 * 0 4 9 7 9 1 1 0 100 o + o 1 9 8 6 1 0 2
Purified by distillation. Purified by recrystallization. Reagent used in 1.11 concentration for oximation. Calculated on basis of one carbonyl reacting per molecule.
perchloric acid. For the assay of those compounds which gave rise to nontitrable oximes, a blank was prepared and titrated in the same ~ a y .For the determination of slow reacting carbonyls, a smaller volume of a more concentrated reagent solution was used. The potentiometric titration was carried out Kith a Beckman Model H-2 p H meter equipped with a glass electrode and a sleevetype calomel electrode, in which the saturated aqueous potassium chloride solution was replaced by 0.0251 lithium chloride i n acetic acid. The results of these analyses are shown in Table 111. The data shorn that the method seems to be as satisfactory as any proposed previously. Because of its total insensitiveness t o organic acids, the relative stability of the reagent solution employed, and the convenience of its potentiometric end point, the method is ivell suited for anal? ais of complex organic mixtures. ACKNOWLEDGMENT
This study was supported in part by a grant from the Research Committee of the Graduate School from funds supplied by the Wisconsin Alumni Research Foundation. LITERATURE CITED
10 20 30 40 50 60 70 8 0 90 100 110 120 TIME
IN
HOURS
Figure 5 . Rate of decomposition of hydroxylammonium acetate in 0.541 solution in acetic acid Plotted a s first-order reaction
(1) Bryant, W. 11.D., Smith, D. AI., J . Am. Ckem. Soc. 57, 57-61 (1935). (2) Eitel, .I.,J . p r a k t . Chem. 159, 292-302 (1942). (3) Fritz, J. S., Fulda, 11.O., A s . i L . CHEY.25, 1837-9 (1953). (4) Knight, H. B., Swern, D., J . Am. Oil Chemists' S O C .26, 366-TO (1949). ( 5 ) Perret, J. J., H elc. Chim. A c t a 34, 1531-43 (1951). (6) Royals, E. E., "Advanced Organic Chemistry," Prentice-Hall, Kew York, 1954. (7) Smith, D. l l . , llitchell, J., Jr., AXAL.CHEM.22, 750-5 (1950). (8) Suratt, E. C., Proffitt, J. R . , Jr., Lester, C. T., J . Am. Ckem. SOC. 72, 1561 (1950). RECEIVED f o r review November 16, 1955, Accepted February 23, 1956. Based in part on a thesis submitted January 1955, b y C. H . Barnstein, in partial fulfillment of the requirements f o r t h e degree of master of science.
