Table VI1 is 10% for EPON 1001. Maximum relative accuracies of 4 and 5% are observed for the diols and triols, respectively. Advantages of NMR. There exists a number of analytical techniques to characterize epoxy resins and polyols (IO, 2 1 ) . Among these techniques can be found various methods for the determination of the repeat unit, chiefly through titrimetric analysis (epoxide equivalent for the epoxies and hydroxyl number for the polyols). While these methods prove to be superior for high molecular weight resins where the NMR ratios for calculating n are prone to greater inaccuracies as reflected by a large value of E , the methods are still subject to a multitude of interferences from chemically foreign materials and an inaccurate presumed average molecular structure. Hence, the presence of foreign species which offsets the accuracy and precision B. Dobinson. W Hofmann. and B P. Stark. "The Determination of Epoxide Groups." Pergarnon Press, New York. N.Y., 1969. D. J. David and H. B. Staiey. "Analytical Chemistry of the Poiyurethanes," Vol. X V I , Part I l l of "High Polymers," H. Mark, Ed., Wiley-lnterscience, New York. N.Y., 1969, Chapter V , pp 278-309.
of the NMR analysis also contributes to the error of the titrimetric analysis. However, unlike the titrimetric method, one can selectively choose the areas in the NMR approach to minimize this interference. Furthermore, the NMR approach has the potential of being able to quantify partially cured epoxies and polyols.
CONCLUSION The precision of measuring the number of repeat units, n, has been demonstrated to be dependent upon the precision in measuring the PMR areas and upon the choice of ratioed areas. The approach is basically applicable to any polymer whose NMR spectrum exhibits a t least two linearly independent areas and proves to be particularly useful when more conventional methods of analysis fail. It has been experienced that the values of n chosen by a minimal standard deviation and coefficient of variation compare most favorably with n values obtained via epoxide equivalents or hydroxyl numbers. Received for review October 6, 1972. Accepted February 21, 1973.
Use of Hexafluoroacetoneand Fluorine Nuclear Magnetic Resonance to Characterize Active Hydrogen Compounds Gordon
R. Leader
Pennwalt Corporation, King of Prussia. Pa. 79406
Hexafluoroacetone in ethyl acetate solution reacts readily with small amounts of organic compounds containing active hydrogen groups to form adducts containing the probe group -C(CF3)20H. The 19F spectra of these solutions show lines which, in their positions and responses to changes in test conditions, are characteristic of the kind of functional group present and, in finer detail, of the compound tested. Hydrogen bonding abilities of the unusual -C(CF3)20H probe group enable it to interact with the solvent and all groups in the compound tested which can be involved in hydrogen bonding. Chemical shifts are given for hexafluoroacetone adducts of 125 alcohols and amines, illustrating many multifunctional and structural types, and interpreted to show how hydrogen bonding affects the discriminating powers of this NMR reagent.
A dilute solution ot' hexafluoroacetone (HFA) in ethyl acetate can serve as a convenient NMR reagent for the detection 01 l'unctional g r o u p with active hydrogen atoms in organic compounds ( 1 ) . The general reaction occurring upon simple mixing a t ambient temperature is as follows:
where M is 0, S,or N. By means of this reaction, six fluorine atoms are introduced for each active hydrogen in the compound tested. The 19F NMR spectra of the adducts formed generally show narrow lines in a 10-ppm spectral range which can be sensitively detected and whose chemical shifts are characteristic of the compound being tehteci. The HFA adducts of active hydrogen compounds differ fundamentally from other compounds such as alcohol trifluoroacetates which have been used as tagged derivatives for study by NMR in that they are transient species involved in reactions whose equilibrium conditions determine their chemical shifts. The -C(CF3)20H group which they contain is weakly acidic ( 2 ) and can hydrogen bond strongly to electron donor atom> in the same or other molecules. With a simple molecule such as ethanol, such H bonding of the adduct present at low concentration is with the solvent ethyl acetate (EtAc). When intramolecular H bonding is possible as in the adduct of CH30CH2CH20H. it may exist as n rapidly cxchanging mixture of the solvent bonded and intramolecularly H bonded forms as in (2) and hence gives an averaged chemical shift tor the t'luorine-containing species involved. CH30CH CH OC CF3 2 2 1 OH E t A c
2. CH30CH CH OC'CF32
2 l
i _ _ .
+
EtAc
--HO
(2) W. J. Middleton and R. V. Lindsey, Jr., J. Amer. Chem. SOC., 86, (1) G. R . Leader, Anal. Chem.. 42, 16 (1970)
1700
ANALYTICAL CHEMISTRY, VOL. 45, NO. 9, AUGUST 1973
4948 (1 964),
In some cases, the equilibria such as Equation 2 are shifted far to the right resulting in a stable intramolecularly bonded adduct, and show little effect from the solvent bonded form or from interchange. In other cases, however, the solvent bonded and intramolecularly H bonded forms may be of comparable stability and coexist, giving an averaged adduct line position. These averaged lines will be sharp when the interchange reaction is rapid or may become broadened if interchange occurs at a n intermediate rate. In general, however, the HFA adducts have sufficient intrinsic stability or are sufficiently stabilized by hydrogen bonding so that adduct molecule lifetimes are longer than the NMR observation time and sharp adduct lines are observed. Since the reactions affecting adduct chemical shifts are, under the conditions normally used, controlled only by temperature and the chemical properties of the solvent and compound tested, they result in definite chemical shifts, independent of minor variation in concentrations, and useful as identifying characteristics of the compounds tested. The HFA reagent has unique capabilities in application to compounds containing multiple active hydrogen functional groups and electron donor atoms. With many such compounds, provided that molecular complexity is not too great, multiple adduct line patterns can be obtained which are characteristic of the given compound and which can often be shifted by easily produced changes in experimental conditions to give further confirmation of the presence of a given compound. The intramolecular H bonding which adducts of some compounds can undergo is of special significance because it often causes the observed chemical shift for the line or lines of a given compound t o be affected by parts of the molecule which are a t a considerable distance from the reacting functional group. In the case of simple adducts from compounds that contain only a single functional group and are not able to undergo intramolecular H bonding, the adduct line positions fall into fairly well defined parts of the spectrum, each characteristic of a given functional group. However, even these ranges for individual functional groups overlap to a considerable extent, and in cases where intramolecular H bonding is possible, the large upfield shifts which this produces can move the adduct line from a given functional group out of the range normally characteristic of such groups. This behavior complicates the interpretation of an adduct line from an unknown compound which has been observed at a given position in the spectrum. Such interpretation is facilitated by knowledge of the behavior of a large variety of known materials under the various possible test conditions. In this paper, the chemical shifts for HFA adducts of 125 compounds, and interpretations of the effects which they show, are given to provide such information. In a few cases, A values reported in ( I ) are repeated for comparison with the new data given. EXPERIMENTAL Apparatus. The 19F S M R spectra were obtained a t 32 "C using a Varian DP-60 instrument operating a t 56.44 MHz. Trifluoroacetic acid in a 1.5-mm capillary was used as an external standard, and spectra were calibrated with side bands of the TFA resonance produced by field modulation. Reagents. Hexafluoroacetone solution was prepared by passing the gas (Allied Chemical) into reagent grade ethyl acetate cooled to 0 "C until the required weight was absorbed. For the work reported here, 0.25-0.3M solutions of' HFA were used since such solutions retain dissolved HFA better and give smaller effects of concentration changes on chemical shifts than do the 0.5M solutions prescribed in ( 1 ) . The solution of HFA in ethyl acetate used should also contain about 0.05M H20. The chemicals used were
from commercial sources and were used without further purification. The compounds 2,2-bis(trifluoromethyl)-l,3-dioxolane(bp 105 "C) and hexafluoroacetone dimethyl ketal (bp 86 "C) were prepared from HFA as described by Simmons and Wiley (3). Procedure. Solutions for testing were prepared by addition of 5 p1 or 5 mg of the compound being studied to 0.6-1.0 ml of HFA solution. In the actual testing of unknown compounds, the adduct line position for a compound of molecular weight about 100, and having one unhindered active hydrogen group can usually be determined with as little as 0.1 mg of sample. A given compound should normally be tested under one or more of the following experimental conditions: 1. Excess of HFA present sufficient to react with all functional groups containing active hydrogen. 2. Excess of HFA present and strong acid in sufficient amount to neutralize =NH, -NHR, or -NR2 groups if present. 3. HFA present in amount sufficient for reaction with only fractional amounts of the active hydrogen functional groups. A large excess of adduct forming compound, however, should be avoided. By testing under these three sets of conditions, all of the characteristic adduct lines which a given compound is capable of forming can be detected. The adduct spectrum observed under condition 1 may remain unchanged under conditions 2 and 3 or may be altered by neutralization and intramolecular H bonding effects. The information thus obtained furnishes useful clues for establishing identity of an unknown compound. In cases where the entire available sample must be used for testing under condition 1, condition 3 can be established in the same test solution by addition of some other active hydrogen compound (whose own adduct line can be recognized and does not interfere) in small controlled amounts so that free HFA is all reacted. The size of the adduct lines formed under condition 1 relative to the size of the line due to free HFA usually furnishes enough information to show how the relative amounts of HFA test solution and compound must be changed to achieve condition 3, and similarly, if TFA is used as the acid for neutralization to produce condition 2, the size of its singlet a t about -1.4 ppm allows estimation of its relative molar concentration. Neutralization of acidic compounds such as glycolic acid, when it is desired to produce adducts of the anion form of such compounds, is best done by the use of triethylamine. A scan of the 19F spectrum of the prepared test solution shows a singlet a t -2.32 ppm from TFA(ext) due to free HFA, a singlet at +5.02 ppm due to HFA(H,O), and one or more features in the range -4.3 to +6 ppm due to -C(CF3)20H in the adduct of the compound being tested. The latter is usually also a singlet or narrow multiplet because the long range coupling of CF3 groups to protons on the carbon attached to the reacting functional group is normally only about 0.8-1 Hz. Coupling to nitrogen and exchange effects may cause a further increase in line width to 5-10 Hz in some cases, e.g., with secondary amines. The adduct spectrum can in some cases appear as an A3X3 or A3B3 pattern when the reacting functional group is on an asymmetric carbon atom. The use of free HFA and HFA(H20) as internal standards for measurement of adduct line positions has been continued with A and A' defined as in ( I ) . The free HFA and HFA(H20) lines have the advantage of being a constant feature of the HFA-EtAc solution spectrum and referencing to them serves adequately to designate the approximate location of compound adduct lines. Positive values of A denote adduct line chemical shifts downfield from HFA(HzO), whereas positive values of A ' denote adduct line chemical shifts upfield from HFA. This convention is used because the great majority of adduct lines fall in the region between HFA and HFA(H20). The positions of both the HFA and HFA(H20) lines relative to TFA(ext) move upfield only about 0.15and 0.11 ppm, respectively, as the concentration of HFA changes from 0.13to 0.54 molar. Adduct lines frequently respond to HFA concentration changes as does the HFA(H20) line, and hence the A values tend to be more nearly independent of concentration than do line positions relative to TFA(ext). In general, it is desirable to reference an adduct line to an internal standard which is itself an adduct, since then both are similarly affected by the electron donor population of the solution. For most accurate measurement of chemical shifts of adduct lines falling in the spectral region near HFA, the adduct of a mercaptan such as n-butyl mercaptan can advantageously be used as the internal standard. (3) H. E. Simmons and D. W. Wiley. J. Amer. Chem. SOC.,62, 2200 (1960).
ANALYTICAL CHEMISTRY, VOL. 45, NO. 9, AUGUST 1973
1701
Table I. Chemical Shifts Relative to HFA(H2O) or HFA for Representative Compounds to Illustrate General Factors Affecting A and A' Compound AQ 1. CH3CH2CH20H 2.57 1.51 2. C H ~ O C H ~ C H Z O H 1.25 3. C ~ H ~ O C H ~ C H Z O H 4. CH30CH2CH2CH20H 2.38 1.90 (1.74) 5. HOCH2CH20CH2CH20H 0.51 6. ( C H ~ ) Z N C H ~ C H ~ O H 7. HN(CHzCH20H)2 (1.72)2 2.06 8. N(CH2CHzOH)3 -0.86 (NH A ' ) 9. CH3CH2CH2NHCH2CH2CH3 4-0.16 (NH A ' ) , 2.52 (OH) 10. HOCH2CH2NHCH2CH20H 11. C H ~ O C H ~ C H Z N H C H ~ C H ~ O+1.10 CH~ (NHA') 2.39 (OH), 3.50 ("2) 12. HOCH2CHzNH2 0.51 I3.151 13. (CH3)2NCHzCH20H 14. ( C ~ H ~ ) ~ N H C H Z C H ~ N H ~ 2.44 [3.55] 3.88 (3.1 1)2(2.54) 1 [3.42] 15. HzN (CH2)2NH(CH2)zNHz -0.04 (NH A r ) 4.08 (2.52)2(1.51)1[3.79] 16. H2N (CH2)sNH(CH2)3NH2 -0.70 (NH A r ) 2.50 (1.14) [2.86] OH 17. H2NCH2CH2NHCH2CH20H 3.86 (3.36) 13.431 NH2 +0.05 (NH A ' ) a A denotes adduct line chemical shift in ppm downfield from H F A ( H 2 0 ) . A' denotes adduct line chemical shift in ppm upfield from HFA.
For quantitative studies, the compound 2,2-bis(trifluoromethyl) 1,3-dioxolane was found useful. An ethyl acetate solution containing about 0.2M dioxolane and 0.2M HFA shows a narrow band for the dioxolane resonance a t +3.08 relative to TFA(ext). A comparison of the size of the dioxolane band (from an accurately known concentration) with that of free HFA in the same solution allows the concentration of the latter to be determined. Finally, comparison of the integrals for HFA resonance in this standard solution with that for an ethyl acetate solution containing HFA only, measured in a matching tube and under the same conditions, allows the HFA concentration of the latter solution to be determined.
RESULTS AND DISCUSSION The location of the HFA adduct singlet for a compound depends primarily on the reacting functional group present and, in cases where no electron donor site is present in the reacting molecule, falls in characteristic ranges for each type as shown in ( 2 ) . Considerable deviation from the normal position of A for a given functional group may occur when other substituents having strong inductive effects are present near the reacting functional group, and large shifts can also occur as a result of intramolecular H bonding. Where this is possible, upfield shifts as large as 2.5 ppm can occur. The shift appears to be due to bond angle changes or effects associated with ring formation in the H bonded configuration, as suggested by the marked difference in chemical shifts (TFA ext.) that is observed between hexafluoroacetone dimethyl ketal (I) and 2,2-bis(trifluoromethyl)-1,3-dioxolane (11) in dilute solution in ethyl acetate.
( I -2 23
(11) ~ 3 . 0 7
General Factors Affecting A a n d A'. Table I contains a listing of A and A ' values for selected compounds which illustrate the general factors that determine the chemical 1702
shifts of HFA adduct lines and which will be dealt with in the following discussion. In this and the following tables, A values given without qualification are those observed when excess HFA is present. A values in parentheses refer to adduct lines of compounds with two or more OH, >NH, or NH2 groups, observed when the compound equivalent concentration exceeds that of HFA and where partially reacted compounds and H bonded adducts, as well as the usual completely reacted adducts, are possible. The use of subscripts 1 and 2 with A values in parentheses refer to mono and diadducts, respectively. A values given in brackets are those observed with excess HFA, and TFA present in sufficient amount to protonate any N H < , RNH-, or R2N- groups present. Compounds 1 and 2 in Table I illustrate the generally observed decrease in A that occurs when intramolecular H bonding to -OR is possible. The nature of R affects the fraction of time which such adducts spend in the H bonded configuration, and also the shielding experienced by the -C(CF&OH group in this configuration, resulting in sensitivity of A to the nature of R as shown by 2 and 3. The ring structure formed through hydrogen bonding in 3 contains 7 atoms. The effects of such hydrogen bonding are still present, though reduced in amount, when the ring contains 8 atoms as in 4 where the electron donor site is -0-. If the electron donor site is >NH or R&, the effect of hydrogen bonding is actually larger for the 8-membered ring than for the 7 , as shown by 15 and 16 in Table I. In general, the effect on A of intramolecular H bonding is dependent on both the nature of the electron donor and on the size of the ring formed, so that when A shows little H bonding effect, it is indicative of weak electron donor properties of a potential electron donor site and/or unfavorable geometry. In 5, HFA can be attached at two functional groups which are equidistant from an electron donor site in the same molecule. Here each attached HFA must share access to this electron donor site with the other one, each spends correspondingly less time in the H bonded configuration, and, hence, there is less effect on A than is shown in 3. In the monoadduct of 5, the HFA a t a single -OH position has greater access to the central -0-, but not exclusive possession of it since it must still compete with the free -OH group on the other end of the molecule which can also hydrogen bond to some extent with -0-. As a result, A for the monoadduct of 5 differs from the 5. value for 3. The differing values shown for 6, 7 , and 8 are illustrative of this same effect, as are the A values for many other multifunctional compounds which are given in the later tables. A further effect of general importance is illustrated by compounds 9, 10, and 11. In 9, A' shows the typical value for a secondary amine in which HFA attached a t -NHcannot undergo intramolecular H bonding. In 11 where such bonding is possible, a large upfield shift indicative of it occurs. In 10, an upfield shift for the NH adduct line is also observed indicating H bonding in spite of the fact that the OH groups are also combined with HFA and give a separate adduct line a t A = 2.52, a normal primary alcohol value. These results suggest that -OH and NH2 groups, even when reacted with HFA, still retain some ability to serve as electron donors for H bonding with -C(CF3)20H attached elsewhere in the same molecule, whereas -"groups when reacted with HFA do not. Further evidence of this effect is shown by 12, where the mutual interaction of OH and NH2 groups with attached HFA, by each being partially H bonded to the other, can account for the fact
ANALYTICAL CHEMISTRY, VOL. 45, NO. 9. AUGUST 1973
that A in each case shows some upfield shift as though intramolecular H bonding were occurring. Compound 13 shows that when HFA is attached at OH and can H bond to a tertiary nitrogen on the /3 carbon, a large upfield shift in the adduct line position occurs. When acid is added to iuch a solution, the following rapid equilibrium exists: R2NCH CH OC(CF312 I
*
2 1
+ H+=
HO R2NH'CH
131 CH OC(CF3)2
2 1
OH,,,EtAc
Under these conditions, a single adduct line is observed which has the averaged chemical shift for species I and I1 and whose position depends on the relative amounts of each. As increasing amounts of trifluoroacetic acid are added to a 0.08M solution of 2-dimethylaminoethanol in ethyl acetate (0.25M in HFA), the single adduct line moves steadily downfield from A = 0.5, reaches a limiting value of A = 3.15 when 1.2 moles of acid are present for mole of compound and shows little further change with excess acid. Similar behavior is shown by 14 which requires a larger excess of acid to reach a limiting value for A . In general, compounds such as 13 and 14 require a variable amount of excess acid to reach a limiting value of A , depending on the stability of the intramolecularly H bonded form and the nature and number of basic centers in the molecule. It may be impractical sometimes to reach the limiting value and, for most purposes, it is sufficient to observe A for such a compound with acid present in small molar excess over the compound concentration, since this is roughly characteristic of the compound even though not a limiting value. In determining A for the protonated form of compounds such as 13 and 14, it is desirable to add acid to the compound before addition of HFA since conversion of the H bonded form to the protonated form may be slow if the former is first produced. It is of interest also to compare the A values for 13 and 14 with those observed when the protonated amine function is not present as in n-butanol (A = 2.58) and n-butyl amine (A = 4.00). This comparison shows that if a protonated basic center in a molecule is near an -OH group, it increases A for that primary OH group above the value normally characteristic of straight chain primary alcohols, whereas if it is near an -NH2 group, it decreases A for that NH2 group below the value normally characteristic of straight chain primary amines. The multifunctional compounds 15-17 illustrate how the adduct spectra of such compounds appear as the relative amounts of HFA and compound in the test solution are varied. No. 15, diethylenetriamine (DET), with HFA/ DET molar ratio >3.5, is reacted at all three functional groups and shows an -NH2 adduct line somewhat broadened a t A = 3.89 and a broadened =NH adduct line at A' = -0.04. When the HFA/DET ratio falls below 3, one observes in addition to the line at 3.89, a sharper line a t A = 3.11 corresponding to -NH2 in molecules which have HFA on the -NH2 groups H bonded to the unreacted =NH. As the HFA/DET ratio decreases further (2-1.5) the line at A = 3.89 finally disappears, the line at A = 3.11 grows larger, and a new weak line at A = 2.52 appears. The latter corresponds to monoadduct molecules in which HFA is attached a t just one -NH2 position and H bonded to =NH. It shows a larger upfield shift than the diadduct, because here one -C(CF3)20H has exclusive use of the =NH position for H bonding except for the weaker competition which'it receives from the free -NH2 group on the
other end of the molecule. As the HFA/DET ratio decreases further to one and below, the diadduct line at 3.11 decreases in size and the line at 2.52 increases but their positions remain unchanged. With HFA/DET = 2 or above, the addition of acid in sufficient amount to protonate the =NH group prevents H-bonding to this position and also introduces inductive effects resulting in a single adduct line for -NH2 at A = 3.42. No. 16, the next higher homolog of DET, shows corresponding adduct lines, the A or A' values of which are all changed because of the additional -CH2- groups. When -OH and -NH2 groups and a n electron donor site are simultaneously present in a molecule as in 17, a greater number of adduct lines is observed, but their origins and positions, which change as experimental conditions are changed, can be readily interpreted and assigned as indicated. Interference by Intramolecular H Bonding. Some compounds, such as methyl salicylate, although they contain a functional group with an active hydrogen atom, fail to show adduct formation with HFA under the usual mild conditions of this test because of existing strong intramolecular H bonding. Other examples are o-hydroxyacetophenone and 1,3-dihydroxy-2-propanone.o-Nitrophenol does not give an adduct line, but the para compound does, indicating interference by H bonding in the former. In these cases, the acidity of the phenol also inhibits adduct formation and the even more acidic phenols such as 2-chloro-4 nitrophenol and 2,3-dichlorophenol do not show adduct formation. Cases may exist, as in the compound ( C H S ) ~ N C H ~ C H ~ C H ~where N H ~ ,the intramolecular H bonded form of the molecule is comparable in stability to the adduct with HFA. Under these conditions, very much broadened adduct lines may be observed if the rate of interconversion of the HFA adduct and the internally H bonded compound occurs a t an intermediate rate. A sharp adduct line is best obtained in such cases by preventing intramolecular H bonding by addition of acid. H Bonding to Sulfur. Hydrogen bonding to sulfur as the electronegative atom is known to be weak ( 4 ) . The observed A value, 2.45, for the adduct of Z-methylthioethan01 in ethyl acetate shows only a small change from the value for propanol, 2.57, indicating little effect from hydrogen bonding to sulfur. This is due to stronger hydrogen bonding of -C(CF3)20H to the solvent. This competition from the solvent can be removed by use of chloroform instead of ethyl acetate and, under these conditions, the adduct line positions for thioethers show upfield shifts attributable to hydrogen bonding as do the corresponding oxygen compounds. HFA is less soluble in chloroform than in ethyl acetate, but can be used in CHC13 a t a concentration of about 0 . 1 ~ Under ~. these conditions the singlet due to free HFA appears a t -3.52 ppm and that due to HFA(H20) a t +3.90 relative to TFA(eqt). The A values found for solutions containing 5 p1 of various compounds added to 1 cm3 of 0.09M HFA in CHCl3 are shown in Table 11. The corresponding A values for ethyl acetate solutions are included for comparison. It is evident from Table I1 that the thioethers in chloroform show a substantial decrease in A as compared with the value for alcohols which cannot show intramolecular H bonding. The decrease, however, is only about one third as large as that shown by the comparable methoxy compound. Different shielding effects of the oxygen and sulfur ( 4 ) J C Davis, Jr , and K K Deb, 'Advances in Magnetic Resonance, ' Vol 4 , Academic Press, New York, N Y , 1970, p 203
A N A L Y T I C A L C H E M I S T R Y , VOL. 45, NO. 9, A U G U S T 1973
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Table 1 1 . Chemical Shifts Relative to HFA(H20) for Some Alcohol Adducts of HFA in CHC13 and CH3COOC2H5 Compound
CHZCH~CH~OH CH~CHZCH~CH~OH CH30CH2CH20H CH3SCH2CH20H CZH~SCH~CH~OH
ACHCI3
AEtAc
2.74 2.75
2.57 2.58 1.51 2.45 2.44
0.56
2.05 2.00
atoms, as well as the difference in H bond strength may contribute to the change in 1 observed for the ether and thioether compounds. The methoxy compound in CHC13 solution exhibits a change in 1 due to H bonding of 2.18 ppm, as compared with a change of 1.07 ppm observed with ethyl acetate as solvent. The use of a non-H bonding solvent such as CHC13 evidently furnishes a convenient means of accentuating intramolecular H bonding effects on adduct spectra. Primary Alcohols and Glycols. The 1 values for primary alcohols and glycols are given in Table 111. In many cases, these are close to 2.5, but they can show substantial deviations frorn this value due to substituents having inductive effects or which can permit intramolecular H bonding. The latter produces a considerable decrease in 1,the magnitude of which is affected by the nature of the electron donor site, the group R attached a t the electron donor site, and even by groups on the chain intervening between the attached -C(CF3)20H group and the electron donor site. In cases where a nearly normal value for .lis observed despite presence of an electron donor site suitably located in the molecule for intramolecular H bonding, this result indicates poor electron donor capabilities of this group relative to that of the carbonyl group in the solvent ethyl acetate. The considerable difference in 1 values shown by furfuryl alcohol and tetrahydrofurfuryl alcohol is noteworthy and indicates that the ring oxygen in the former compound is a poor electron donor, probably because of resonance of its electron pairs with the double bond r electrons. A similar cause results in little observed effect of intramolecular H bonding in the adducts of ArOCHzCH20H compounds. However, some H bonding does evidently occur in these cases as shown by the detectable effects of substituents in the aromatic nucleus. An interesting difference is observed also in the behavior of RSO2CHzCHzOH and RSOCHzCHzOH compounds. The former give single adduct lines of normal width at about 1 = 2.6 which indicate that there is no significant intramolecular H-bonding to > S o n . In contrast to this, the sulfinyl compounds show A3B3 adduct line patterns a t about 1 = 2.04. This indicates that greater H bonding occurs to the sulfinyl group, and also that asymmetry a t the electron donor site to which intramolecular H bonding occurs can cause CF3 group nonequivalence, as does asymmetry at the carbon to which the reacting functional group is attached. Compounds of the type RNHCHzCHzOH, with large excess of HFA present frequently give >NH and -OH adduct lines which are severely broadened because of rapid interchange reactions. With a small excess of compound present (Compound/HFA ratio slightly larger than l), the line for the internally H bonded adduct a t OH is more readily observed. It is sharp and is a t 1 = 0.50 for R = CH3, 0.55 for R = C2Hs, 0.48 for n-C4Hg-, 0.5 for i-C3H7. and a t 1.03 for R = t-C4H9. The effect of steric hindrance by the t-C4H9 group in reducing intramolecular H bond1704
Table 1 1 1 . Chemical Shifts Relative to HFA(H20) for Primary Alcohol and Glycol Adducts in Ethyl Acetate A
Compound
2-Fluoroethanol 2-Chloroethanol 2-Bromoethanol 1,1,3-Trihydroperfluoropropanol
P-Hydroxypropionitrile a-Hydroxyethyl acetate N- Acetylethanolamine 2- (Methy1thio)ethanol 2-(Ethy1thio)ethanol 2-Chloroallyl alcohol 3-Chloro-1-propanol 1,3-PropanedioI
2.50 2.40 2.38 2.30 2.46 2.40 2.62
2.45 2.44 2.46 2.53 2.46 (2.22)
2,2-Dimethyl-l,3-propanediol 2,2-Diethyl-l,3-propanediol 2-Methyl-2-nitro-l,3-propanediol
2.65 (2.05)
@,P‘-Dihydroxyethyl sulfide 2-Butyne-1,4-diol 2-Methylsulfonyl ethanol 2-Ethylsulfonyl ethanol 2-Methylsulfinyl ethanol 2-Ethylsulfinyl ethanol
2.45
2,2,3,3,4,4-Hexafluoro-l,5-pentandiol 1 , l ,1-Tris(hydroxymethy1)ethane 1. l ,1-Tris(hydroxymethyl)propane
Pentaerythritol 2-Methoxyethanol 2-Ethoxyethanol 2-(2-Ethoxyethoxy)-ethanol
2-n-Propoxyethanol 2-n-Butoxyethanol 2-Allyloxyethanol 3-Methoxy-1-propanol 2-Benzyloxyethanol 2-Phenoxyethanol 2-(4-Methylphenoxy)ethanol 2-(4-Chlorophenoxy)ethanol
2-(4-Methoxyphenoxy)ethanol 2- (4-Nitrophenoxy)ethanol 0-(2-Hydroxyethyl)glycolamide
Furfuryl alcohol Tetrahydrofurfuryl alcohol 3-Hydroxy-2-methyl-4-pyrone N - (Hydroxymethy1)phthaiimide
Ethyl glycolate
Methyl hydracrylate imine 2-Dimethylaminoethanol 2-Dimethylamino-2-methyl-1-propanol 2-Diethylaminoethanol 2-Di (n-buty1)aminoethanoI 2-Di (Lpropy1)aminoethanol N- Hydroxyethyl-4-propanol piperidine N- Hydroxyethyl morpholine Triethanolamine Tetrahydroxyethyl ethylenediamine N - (2-Hydroxyethy1)ethylene
0
2.72 (2.04) 2.54 2.54 2.62 2.57 2.06 2.02 2.25
(A3B3) (A3B3)
2.59 2.67 2.56 1.51 1.25 1.51 1.32 1.31
1.59 2.38 1.75 2.43 2.40 2.45 2.37 2.51 2.22 0.82 (-CONH2 1) 2.69 1.49 2.19 1.67 2.28 2.09 1.02 0.57 [3.101 1.83 [3.42] 1.07 [3.15] 1.19 13.121 2.52 [3.64]
0.47 [3.01In 0.50 [3.00] 2.06 [2.75] 2.06 [2.86]
The non-H bonded OH also gives a line at A = 2 60
ing to RNH- is apparent in the 1 value for this last compound. When acid is present in sufficient amount to protonate the RKH group, 1 for the adduct lines of RXHz+CH2CH20H is about 3.0 in all cases. In compounds of the type R2NCH2CH20H (Table 111), large effects of the nature of R are also evident and remain. even with acid present. when R is i-C3H.;-.
ANALYTICAL C H E M I S T R Y , VOL. 45, NO. 9 , A U G U S T 1973
Table I V . Chemical Shifts for HFA Adducts of Compounds of the Type HOCH2CH2-N-CH2CH20H
R R"
Excess HFA
5,OH Excess HFA Acid
Deficient HFA
CH3 C2H5 i-C3H7 n-C4Hs t-C4Hob C6H5'
1.63 1.87 2 15 1.93 2 61 2.50
[2.92] [2.88] [2.89] [2.88] [2.99] [2.50]
(0.85)i (1.22)1 (1.82) 1 (1.24)i (2.97)i (2.5o)i
+
Table V . Chemical Shifts for HFA Adducts of Secondary Alcohols in Ethyl Acetate A Compound 1,1,1 -Trichloro-2-propanoI 4-Pentyne-2-01 1-p-Fluorophenylethanol 2,6,8-Trimethyl-4-nonanol Ethyl lactate 1,2-Propanediol 1-Methoxy-2-propanol 1-Dimethylarnino-2-propanol
( I When R = H, the observabie adduct line values are 2 . 5 2 , ( 1 . 7 2 ) 2 ( 1 . 0 2 ) ,and [2.67] rather than as reported in ( 7 ) . With the tertbutyl compound, there is a reversal of the usual magnitudes of 5, for mono- and diadduct because the free -CH2CH20H group in the monoadduct comperes more effectively for the electron pair on-NR than does the -C(CF3)20H group on the other end of the molecule when steric hindrance at N is severe. When R = --C6Hs. 1 is affected only slightly by HFA/cpd ratio and by the presence of acid because of very weak electron donor properties of N in this case.
Compounds of the general type HOCHzCHzN(R)CH2CHzOH show characteristic adduct lines for mono and diadducts under appropriate conditions, and the positions of these are also considerably affected by the nature of R as shown in Table IV. Secondary and Tertiary Alcohols. As noted previously ( I ) , secondary straight chain alcohols will frequently give normal narrow adduct lines in the range S = 1.75 to 1.95. Additional examples are given in Table V. If OH is attached to an asymmetric carbon, this will frequently, but not always: cause CF3 groups of the attached -C(CF3)20H to become nonequivalent and will result in an A3X3 or, more commonly. an A3B3 line pattern, still centered a t the usual position, but less sensitively detected than when a single line is formed. (The term A3B3 is used loosely here to denote the two-band partly resolved adduct spectra, frequently looking like two abnormal triplets which are obtained when steric factors cause CF3 nonequivalence. The line structure of these may be influenced by interchange and conformer effects. as well as by coupling constant and chemical shift differences between CF3 groups, so that they are not true A3B3 patterns in the normal sense.) This shortcoming of the HFA reagent for tagging of organic molecules may make it inferior to (CF3CO)pO in some applications as noted by Jung e t al. ( 5 ) . Whole molecule shielding effects, inductive effects of attached groups, and hydrogen bonding effects can also operate in some cases in such a way that secondary alcohols give adduct lines which are considerably removed from the normal range. This is illustrated by: 1.1,l-tri1 = 2.82 (A3B3). ethyl lactate 2.01 chl~~ropropanol-2 (A3B3), and 2.6.8-trimethyl-4-nonanol2.32. Similar remarks apply to the adducts from tertiary alcohols. which fall in the range 1.2-1.4 for simple cases, but which have been observed at considerably higher v d u w in others such as ethyl iu-hydroxyisobutyrate 2.60, citric acid :)j.G9. and 3-methyl-1-pentyne-3-01, 1.71 (A3X3). Jn the lnttcr vase.. -OH is on an asymmetric carbon atom and hence C Fs g r w p nnnequivalence is observed as with secondary nicohols. P r i m a r y Amines. The S values for adducts of primary amines which cannot undergo intramolecular H bonding, or which were not studied under conditions that favor occurrence of this. are shown in Table T'T. It will be noted ( 5 ) G. Jung. 1Y Voelter. E. Breitrnaier. a n d E. Bayer, A n a / . Chim. Acta, 5 2 , 382 ( 1 9 7 0 ) . '
1-Amino-2-propanol
2.82 (A3B3) 1.79 (A3B3) 2.22 (A3B3) 2.32 2.01 (A3B3) 1.71 (A3B3) 2 51 (Pri. OH) 0.69 (A3X3; 122 H P ) 0 56 (A3X3; 154 Hz) [2.93] (A3X3; 112 Hz) 1.68 (A3X3; 86 Hz) 3.86 ("2)
Quartet separation at 56 4 MHz. CF3-CF3' coupling is 6-9 Hz in these spectra.
A3X3
Table V I . Chemical Shifts Relative to HFA(H20) for HFA Adducts of Amines in Ethyl Acetate (no intramolecular H bonding) NH2 on primary carbon 1 Ethylamine I sobutylam ine N-Octylamine 1.6-Hexane diamine P-Phenyl ethylamine 4-Aminomethyl piperidine 3-Aminomethyl pyridine m-Xylylene diamine 2-Mercaptoethylamine
3.97 3.98 4.02 4.01 3.89 3.96 [3.82] 3.67 [3.47] 3.99 3.94 1.25 (SH 1')
NH2 on secondary carbon
Cyclohexylamine di- Amphetamine 2-Aminobutane NH2 on tertiary carbon tert- Butylamine
3.40 3.43 3.52 (A3B3) 2.22
that the adduct line position moves upfield when -NH2 is located on secondary and tertiary carbon atoms. as is observed also for -OH and -SH.Shielding by groups in the molecule located close to -XH2 frequently has detectable effects on A , and when secondary or tertiary nitrogens are located in the molecule containing an -KHp group, protonation of these causes a change in 1.When electron donor atoms are present and suitably located in the molecule containing an -SH2 group so that intramolecular Hbonding to them can occur, these cause the usual decrease in 1 as shown in Table \TI,and the amount of this is affected by the number of intervening atoms and by the shielding effect of groups in the vicinity of the electron donor site as noted previously for alcohols. Secondary Amines. The A ' values for adducts of secondary amines are shown in Table VIII. These are normally about -0.8 when R in R2KH is a long straight chain alkyl, but a marked deshielding effect is noted when R is -CH3. The tagging group -C(CFs)pOH when attached to > N H can hydrogen bond to electron donor groups in the same molecule which are favorably located, and this produces an upfield shift in the adduct line position as is observed for OH and other groups. When acid is present, the protonation of > N H in simple secondary amines competes more strongly with the reaction with HFA than is the case at -NH2. and if an
ANALYTICAL CHEMISTRY, VOL. 45, NO. 9. AUGUST 1973
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Table V I I . Chemical Shifts Relative to HFA(H20) for HFA Adducts of Amines in Ethyl Acetate (with intramolecular H bonding) With -0- as electron donor atom A 2-Methoxyethylamine 2-Ethoxyethylamine 3-Methoxy-1 -propylamine 3-1sopropoxy-1-propylamine Ethanolamine
Table IX. Chemical Shifts Relative to HFA(H20) for Miscellaneous Hetrocyclic and Aromatic Amines Compound A 1.2-Diaminonaphthalene
2.98 2.72 3.63 3.68 3.60 2.38 (OH) 1.82 2.62 (OH) 3.85 2.55 (OH) 3.23 2.02 (OH)
2-Amino-2-methyl-?-propanol 3-Amino-1 -propanol 2- (2-Aminoethoxy)ethanol
2- Aminopyridine 2-Amino-6-methyl pyridine 2-Amino-3-methyl pyridine 3-Aminopyridine 4-A mi no pyr idine 2,6-Diaminopyridine 3-Amino-1H,1,2,4-tetrazole 2-Aminothiazole 2-Aminobenzothiazole Aminopyrazine 2-Aminopyrimidine
With N as electron donor atom
1,2-Diaminoethane 1,3-Diaminopropane 2-Diethylaminoethylamine 3-Dimethylamino-1-propylamine N- (3-Aminopropyl)diethanolamine 1,3-Diamino-N- (2-hydroxyethy1)propane 4- (3-Aminopropyl)-morpholine N - (2-aminoethyl)-piperazine
3.74 (2.55) 3.93 (2.15) 2.44 [3.55] 1.66 [3.71] 3.80 [3.80] 1.91 [2.86] (OH) [3.82] [2.94] (OH) 1.77 [3.80] 2.03 [3.71] - 1.42 (NH A ' )
Table V I I I . Chemical Shifts Relative to HFA for Secondary Amine Adducts of HFA in Ethyl Acetate 1. Straight chain compoundsno intramolecular ti bonding
Di-N- butylamine Di-N-hexylamine n-Butyl methylamine
A' -0.86 -0.88 -1.79 intramolecular H bondingU
2. Straight chain compounds-with
N-Methyl-/3-alanine I minodiacetonitrile 3,3'-1 minodipropionitrile 2-Methyiaminoethanol
-1.11 -0.10 0.08 - 1.21
3. Cyclic secondary amines
4-Aminomethyl piperidine
- 1.95
Pyrollidine Pyrrole Indole
3.96 ("2 -0.61 1.72 0.90
4. Cyclic amines and ureas-with
Ethylene urea 1,3-Dimethyl urea Ethylene thiourea Pyrollidone e-Caprolactam
intramolecular
A)
H bonding
3.45 (3.94 A ) 2.05 1.47 3.40 (3.95 A ) 1.34
A' for other sec. amines with intramolecular H-bonding is given in Table I ,
1706
4.54ff 3.738 0.78 [1.05] 0.71 [1.21] 0.84 [0.95] 3.40 [3.20] 3.24 [3.40] 2.27 (0.73) 1.55 ("2) 4.75 (NH) 1.23 1.56 1.19 0.94
equivalent amount of acid is present, there is no observable adduct line. In a molecule such as C H ~ N H C H Z C H ~ O the H , HFA attached at OH tends to hydrogen bond to the secondary amine group, and hence interferes with attachment of HFA a t > N H as do free protons. On the other hand, if a good electron donor site is available which allows HFA attached a t > N H to be intramolecularly H bonded, as in CH3NH-CH2CH20CH3, the >NH adduct is stabilized and is not decomposed by acid unless the acid concentration greatly exceeds that of the compound. The upfield shift of the line for HFA at >NH which results from intramolecular H bonding is greatest when the electron donor group does not also hold active hydrogen and is completely available to the >NH group in question as in the example given, but detectable effects of such H bonding are still observed even in cases where the electron donor sites are -OH or -NHz groups which have themselves reacted with HFA. When the > N H group is present in a cyclic structure, as in piperidine (Table VIII-3), this also produces changes in the adduct line position, and such changes depend to a marked degree on the size of the ring, on whether or not the ring is saturated, and on the presence of aromatic nuclei near the reaction site. For some of the compounds in Table VIII, the adduct line positions are also referenced to HFA(H20) and designated by A . Cyclic amides and ureas (Table VIII-4) show the effects to be expected when HFA is attached a t >NH and H-bonded to adjacent carbonyl. Here also a very marked effect of ring size is evident. The Lf values for an additional group of miscellaneous heterocyclic and aromatic amines are given in Table IX. These also show the effect of intramolecular H bonding in most of the cases given. Received for review December 7 , 1972. Accepted March 7 , 1973.
ANALYTICAL CHEMISTRY, VOL. 45, NO. 9, AUGUST 1973
