Thomas J. Lobl
The Chemistry of Nitrosoamides
California Institute of Technology Pasadena, 91 109
The pioneering studies of alkyl nitrosoamidcs were mainlv concerned with their conversion to diazoalkanes. I n the fifties nitrosoamides were recognized as uscful interm~diatesfor the deamination of alkyl amines. During the last twenty years it has been demonstrated that nitrosoamides are synthetically useful as well as able to lend themself to mechanistic studies in a wide variety of areas (1). This paper will briefly review the photochemistry, base and acid catalyzed decompositions, and thermal decompositions of this interesting class of compounds. Emphasis will be given to selected areas in order to point out tho instructive value of nitrosoamides as lecture examples as well as their utility in solvinx - certain research problems. N-Nitrosoamides (I) are prepared by nitrosating a N-alkylamide with sodium nitrite, nitrous anhydride, nitrosyl chloride, or dinitrogen tetroxide (2) [eqn. (1) I.
H' is so large that it is of diagnostic value, although some cxceotions are known (7). ,, Photochemistry of Nitrosoamides
The photolysis of N-nitrosoamides was originally inspired by the synthetic success of Barton (8) in the photolysis of nitrite esters. The first chemical step in the photolysis of nitrosoamides is the homolytic scission of the N-N bond [eqn. (2)l. n NO
/I
CH,C-&-cH,
-
Throughout this paper, %retention
+ %inversion = 100%.
730 / Journal o f Chemical Education
I
II
CH+2-N--CHa 92%
(2)
n
r
-
-
The second step is usually abstraction of a hydrogen from the alcoholic (Q), hydrocarbon (6), or olefinic solvent [eqn. (3)] (9). CHsOH
I n general, the order of stability in I is tertiary carbinamines < secondary carII binamines < primary carbinamines. This R-~-C-R, is in line with the findings of Huisgen (3) who has reported that the rate of decomposition is increased by substituent bulk and is relatively insensitive to electronic effects. Huisgen felt that the bulky groups cause t h e nitroso and the carbonyl groups to adopt a conformationinwhich the probability of rearrangement is greater. N-Nitrosoamides are readily identified by infrared, ultraviolet, and nmr spectroscopy. N-Nitrosoamides have characteristic infrared carbonyl absorptions at 1755-1715 cm-I and N-nitroso absorptions at 15351515 cm-' (for 10 compounds) (2). The distinctive frequency from shift of the amide 1655 (4) to 1755-1715 cm-' on N-nitrosation makes the infrared spectrum useful in determining the extent of reaction. Interestingly, the corresponding N-nitroamides frequently show split carbonyl and nitro bands due to rotational isomerization not seen in the Nnitrosoamides (6). The ultraviolet spectra of aliphatic N-nitrosoamides usually have absorptions a t A,., 242-246 (e 4000-6000), 406-415 ( r loo), and 425435 (c 10) (5 cases) (6). The resonances of protons H' and H " of carbamates like RR1CH1-NH-C02CH2"CH3have been reported by Moss (7) to be deshielded on nitrosation. Usually the deshielding of
+ ON.
CH,-OH
ii
H-C-H
+ RNH-COR
56%
+ RNH-COR 55%
+
RNHCOR
20%
8%
the ne,j, In the third the nitroso radical reacts carbon radical [eqn. (3)] to give kctoncs from alcoholic solvents and oximes, nitroso dimcrs, and nitrites from hydrocarbon or olefinic solvents, Under special circumstances when a r hydrogen is available, an intramolecular abstraction of this hydrogen, analogous to the Barton reaction, has been observed (6, 9-11), For example, and Duckworth studyilig the photolysis of N-nitrosoN-pentylacetamide [eqn, hv
A,N(NO)CH,(CH,),CH,CH, ----,
cans
N-OH AoNH(CH;kCCH8 40% I'
1 !CHs
I
+
\
\
AcNHCH,(CHZ)~NO 516%
(4)
%" '
found 40y0 N-(4-oximino-1-penty1)acetamidc and not more than 16y0 of thc N-(4-nitroso-1-pcnty1)acetamide dimer (9). Interestingly, N-nitroso-N-mcthylvaler-
amide reacts only by iutermolecular hydrogen transfer (9). In another example, Edwards and Rosich (11) found product 111 after photolysis of N-nitroso-2azacyclooctanone (11) in 95% ethanol a t 5'C [eqn. (5) I. N-OH II
of deuterium incorporated) (Id), while decomposition of primary carbinamines appear to incorporate signif25% (15)] amounts of deuterium. The icant [dl general trends secm to hold that the more polar and acidic the solvent, the less the diazoalkane intervention, and the more stable the carbonium ion produced by the loss of nitrogen, the lower amount of diazoalkane produced (16).
-
Deomirntions from Diazatafes
Typical radical reactions likc (3-scission of aliphatic C-C and C-H bonds have becn sccn in thc photolysis of nitrosoamides [eqn. (6)l (6,10,12).
With the proper choice of conditions, base catalyzed decompositions of nitrosoamides can bc adapted to the study of alkyl deaminations (17). In an interesting series of experiments, Moss and co-workers (17-20) studied thc stereochcmical return and solvolysis pathways [eqn. @)] N=O RN-COR
E~,O
II
0
products Cleavage of the C-Ar bond, however, does not seem to occur with amido-radicals even though p-scission of C-H and C-Ar bonds are energetically comparable in the alkoxy radical case (12). I n summary the photolysis of nitrosoamides produce amido-radicals which undergo typical free radical reactions. These amido-radicals arc sometimes useful reaction intermediates for the functionalization of a 7-carbon. Base Catalyzed Decompositions of Nitrosoamides
Base catalyzed decompositions of N-nitrosoamides, carhamates and ureas have been utilized since the discovery of nitrosoamides as a source of diazo compounds. Rather than cover superficially the extensive diazoalkane literature the author prefers to direct the reader to an excellent recent review (IS) and limit further discussion of the base catalyzed decomposition to aspects of deamination. The chemistry of deamination and diazoalkanes are not similar except where the protonation of the diazoalkane to form an alkydiazonium ion occurs [eqn. (7) I. R-CH=N=N
%gL R-CH-N1
I
D
+HX
+ R-CH-ha + R-CHZ+ -HX 1 H
+
+ products
containing deuterium
-X
I
+ NZ+ -X
typical carbonium ion products
(7)
I n deaminations of primary and secondary carbinamines, the intermediate can conceivably go through a diazo form. Therefore, it is important to rule out the intervention of a significant percentage of diazoalkane before mechanistically interpreting the product distribution. One method of driving the equilibrium away from diazoalkane formation would be to carry the reaction out in acetic acid. Commonly decompositions of secondary carbinamines in deuteroacctic acid form 5 6% diazoalkane (as measured by the amount
[
]
R-N=N-0-
+
I
O=N
0
K+
+ &Bu0CORr 11
diazotate salt IV
- +R
I
0
,
-Nz RN=NOH path
0 . and -H
(8) +
R=N,
carbonium V diazoalkanes ions of the diazotate decomposition intcrmcdiatc. Moss (19) found thc partioning of paths a and b to bc dependent on the structure of thc alkyl group. If the alkyl group was secondary, then < 3% diazoalkanc was formed, while if it was primary, thc diazoalkane route was takcu about as often as thc diazonium ion one. Thc diazohydroxidc V is intcrcsting bccausc it is also an intermediate in thc nitrous acid dcamination. Thus, thcre is an opportunity to comparc thc stcrcochemistry of thc products from a "common" intcrmediate derived from thc nitrous acid and thc diazotatc deamination pathways. One important advantagn of starting with thc isolated diazotatc intcrmediatc IV is that there already is an oxygcn attached to thc nitrogen in the molecule. So if thc solvcnt vatcr is enriched with ' 8 0 then the internal-return and thc solvent-derivcd product (19) are distinguishahl~. Moss used this clever procedure to determinc the source of increased inversion' in the product when 2-octyldiazotate was hydrolyzed with wet ethcr instead of water. Isolation and measurement of the 2-octanol demonstrated that the increase in inversion was due nearly entirely to the increased amount of intramolecular inversion. If, instead of adding water to IV an acid chloridc likc benzoyl chloride is added, then onc should get a diazoester VI identical with that generated from thc thermal dccomposition of a nitrosoamidc (18) (eqn. (9)).
II
N, + R+ -0-C-6
-
products
Moss has carried out this reaction for R
=
Volume 49, Number 1 1 , November 1972
cyclo-
/
731
the more polar the solvent the more heterolytic the cleavage (path b). When either alkyl group in compound X I became more bulky, the rate of rearrangement from X I to XI1 increased, and the amount of the homolytic cleavage increased. The PIT-nitrosohydroxylamine system is interesting because one can study the competition between the radical and the ionic pathways as well as gencratc aliphatic radicals at low temperatures. Because of the intervention of free radicals in some dcaminations, all reactions should be examined for evidence of radical intermediates before drawing mechanistic conclusions. Stereochemistry o f the Nitrosoamide Decomposition
After heterolytic cleavage the ion pair X then can close to form ester, react with solvent to form a solvolysis product, rearrange to give rearranged ester or rearranged solvolysis product, or eliminate hydrogen to give olefins. Ester Formotion ond lsomerization Products
Olefin Products
The mechanism of the hydrogcn elimination from the carhonium ion to form an olefin seems to involve a mixture of cis and trans ahstraction pathways. Cohen and Daniewski (42) examined the products from the nitrosocarbamatc decomposition of XI11 a and b and XIV a and b in boiling cyclohexane. In the axial case XIII, they found 92% (XIIIa) and 93% (XIIIh) cis hydrogen ahstraction, while in thc equatorial case XIV thcy found 81% (XIVa) and 76y0 (XIVh) cis hydrogcn abstraction.
x&
+R
X
The formation of esters in polar solvents in nearly all cases (1) proceeds with overall retention of configuration (2, 14). The table gives representative values for the retention of configuration of alkynitrosoamides. In nonpolar solvents the products show a displacement component and therefore the percent retention is not as high (2). Although there is no incisive evidence for a temperature effect on ester retention (59), reaction temperature has been found to play a role in the Retention of Configuration in the Alkylnitrosoamide Decomposition (R = alkyl)
,"
4
Retention
Solvent
amount of rearrangement in the ester products (40) (see figure). The reason for this effcct is not clear. In a related study Miller and coworkers (41) have found no evidence for a temperature effecton the ratio of ester to solvent derived product.
Reference
xm
XN N=O
1 . X = N-C-OEt II 0 Cohen cxplains the differcncc in stercospccificity by pointing out that in the axial casc the countcr ion is in the proximity of only the cis hydrogen (deuterium) and, therefore, cis hydrogen ahstraction or elimination is very high. Howcver, in the equatorial case (XIV) the countcr ion is near both the axial and thc equatorial hydrogens and, therefore, thcy saw a grcater compctition between the cis and the trans hydrogen ahstraction pathways. ina R = D , R r = H inb R = H , R ' = D
Modifications of the Nitrosoomide Reaction
&(cH~)c,H,
Ether Methanol
I
97
52
(1:2)
0
5
I0
15
20
I
Amount of S a c . - Butyl Ester i n lsobutyl E s t w Derived f r o m Rearrangement Temperature versus amount of iromeriration in the nitromamide (A) and nitroamide (81 deeompositionr Taken from reference ( 4 0 ) with the permission of 0. Grirley. Poinh 1-3 from reference (2). Points represent the following decompositions 1 N-(itobutyl)-N-nitro~.3,5-dinitrobenzamid in decalin 2 N-lisabutvll-N-ni1ro.o-3.5-dinitrobenzamid in h e ~ t a n e . 3 ~ - ~ ~ o b u t y l ) - ~ - n i t r o r o - 3 ; 5 - d i n i t t o b ~ ~in ~ ohexone mid A N-(itobutyll-N-nitrora.3.5-dinittobenzamid in other 5 N-(irobutyl)-N-nitro-3,5~dinitrobenzamid in CCh 6 N-(irobutyll-N-nitm-3.5-dinitrobbb11mide in CClr
.
Various analogs of nitrosoamides, such as nitroamides, nitro and nitrosocarbamates, and nitrosulfonamides have been studied (2, 10, 45-45). The decomposition mechanisms of these analogs have also been found to be similar to those outliucd for the nitrosoamides. The general order for the stability of nitroso derivatives is carhamates > amides. In the nitro series the stability order is sulfonamides > carhamate > amide. Comparisons of thc stability of nitrosoamides with nitroamides, etc., show that Nnitro derivatives are more stable than N-nitroso derivatives. As with the diazoester I X it is possible to synthesize XV by an alternate path [eqn. (Id)] callcd thc "salt reaction" (1). -0
NO,
I
R-N-
+1
R-N=N-0-
u
"salt reaction"
0
II
R'-C-CI -70"
I
NO, .
I
.
Volume
49, Number I I, November 1972
/
733
propylcarbinyl and found that indeed the distribution of products are similar from the two methods of preparation. Thus the addition of an acid chloride to a diazotatc offcrs an alternative method of generating the diazoester intermediate of the thcrmal nitrosoamide decomposition. Base catalyzed decomposition of nitrosoamides is also useful in the preparation of vinyl cations. Newman and co-workers (21,62) have treated 5,5-dialkyl-3nitrosooxazolidones with base and obtained vinyl compounds in high yield [eqn. (lo)].
applied to the synthetic modification (50-32) and total synthesis of natural products (33-35). In one clever examplc (34) the nitrosoamide decomposition was used to produce N-bcnzoylmeroquincne ester [eqn. (11)).
Py0A N-NO
Mechanism The mechanism as developed by White (d, 14) and Huisgen (25) is described in eqn. (12).
If 5,5-diphenyl-3-nitrosooxazolidone is treated with 50y0 aqueous sodium hydroxide, a quantitative yield of diphenylacetylene is obtained (22, 23). In general, nitrosoamides offer a synthetically useful pathway to vinyl cation and vinyl derivatives. Acid Effects on the Decomposition of Nitrosoamides
Although the dccomposition rates of nitrosoamides and nitrosocarhamates are known to he increased in acidic solvcnts (S), little work has hcen done to illuminate thc mechanism of the acid catalysis. Thornton (24) found in a study of solvent cffccts on the rate of dccomposition of ethyl N-nitrosoacetamidc that hydroxylic solvcnts (including acetic acid) sccmed to fall in a different category than non-hydroxylic solvents, when dccomposition rates were plotted against theoretical parameters such as solvent dipole moment. Also the decomposition ratcs in hydroxylic solvents wcrc faster than in non-hydroxylic. In addition, acid seems to promote the formation of isomerized products (%,251, and the denitrosation of starting material. In situations'whcre denitrosation is serious, a switch to thc corrcsponding N-nitroamide system would not significantly alter the product distrihution. Thermal Decomposition of Nitrosoamides
The thcrmal dccomposition of nitrosoamides can he discussed in two p a r t ~ a r o m a t i c and aliphatic. Thc chemistry of aromatic nitrosoamides is interesting (involves radicals and bcnzyncs) and is quite different from the aliphatic nitrosoamide derivatives. Hourever, three detailed reviews of aromatic nitrosoamides have hcen published in thc last two years, and so the subject will not be discussed here (26-28).
Evidence for intermediate IX is only indirect, and all cffortsto isolatc diamesters havc failed. The fact that I X cannot hc isolated is evidcncc that rearrangement of VIII to I X is the slow step of the reaction and not thc hetcrolysis of IX. Aftcr the initial rearrangcment, the diazoester IX undergoes hcterolytic cleavage to form the carhouium and countcr ion pair (X) in the solvent cage. The formation of ester by a concerted cyclic rearrangement has been climinatcd by White and Aufdermarsh (14) in the study of the dccomposition of N-nitroso-A-1-phenylethyl-2-naphthamid (carbonyl '80). They showcd that ester product contained a mixture of ' 8 0 in thc ether and carhonyl positions; for example, in acetic acid thc ether/carbonyl l80 ratio was 31/69. The reaction, therefore, must go through a separated ion pair for a finite time, but the time, for ion pair closure must he fast, otherwise the ' 8 0 would he completely scrambled. Although the intervention of radicals has been discounted in the aliphatic nitrosoamide reaction at temperatures near ambient (I), radical intermediates in thc decomposition of aliphatic nitrosohydroxylamines havc been found by Cooley (36) and Koenig (37,38) [eqn. (13)l. 0 O=N
11
RC-
I
N-OR'
rapid
0
11
RCO-N=N-OR'
(13)
Decomposition of Aliphatic Nitrosoamides Of the thrcc main methods of aliphatic deamination ($9) the nitrosoamide decomposition is the most useful from the standpoint of "synthetic utility, stereochcmical correlations, and adaptability to mechanistic studies" (1). The nitrosoamide reaction has been 732
/ Journol of Chernicol Education
(~e-0-
N20
+R'-
v
carbonium ion products
N,
R& v
radical products
.OR,,
+ CO,
Cooley ($6) found that by changing solvent polarity hc got varying ratios of COz/NzOproduced; apparent,ly
Taking the salt of a nitramine and reactingit with an acid chloride gives a one-step route to XV. The diazoxyester XV, however, is not isolahle even when the reaction is carried out at -70°C and decomposes rapidly to products. White and Grisley (43) have shown that the product stereochemistry is similar to that found in the thermal decomposition of the nitrosoamides. For this reason it is believed that there is an overlap in the mechanisms of the thermal decomposition with the "salt reaction" at the diazoxyester stage. The advantage of the "salt reaction" over that of the diazotate method for the preparation of diazoester derivatives is that nitramines are easy to prepare, purify, and handle. A modification of the "salt reaction," where the diazoxyester intermediate has the coordinate covalently bonded oxygen on the &nitrogen from the leaving group, has also been studied (46-49) [eqn. (Is)]
aud its rnrrhanisrn of decornpo.;irio~~ is not arlnloguus to thr nitrowxrnidr rravtion. X t h a n . Sniol\.ako\.. Srkrasov, and Shemyakin (60) have demon8trated that '5N and labeled XVI rearranges first to a Nnitrosohydroxylamine before decomposition to ester products. This result is interesting because Koenig (37,38) has shown that some N-acyl-N-nitrosohydroxylamines rearrange first to hyponitrites before decomposition. Neiman and co-workers, however, suggest that other cases l i e N-nitroso-N,O-dibenzoylhydroxylamine (61) may decompose directly on nitrosation without first rearranging to a hyponitrite intermediate
modifications also provide a method to study the interesting but unstable diazoxyesters and diaeoesters. Acknowledgment
The author wishes to thank Dr. Robert Ferguson for reading the manuscript and for suggesting some improvements. Literature Ciled ( 1 ) Wnm% E. H.. AND Wooococa. D. J., "Chemiatm of the Amino Group." (Editor: PAT*^, S..)John Wilev & Sons, New York. 1968, Ch. 8. ( 2 ) Wxr~., E . H., J . A m r . Cham. Sot.,??, 6008,6011,6014 (1955). ( 3 ) HulsorN, R , A N D RslMLINasn, H., Ann. Chem.. 599, 161 (1956). ( 4 ) N*ammxr, K.. "Infrared Absorption Speotrosoopy." Holden-Day. Ino.. Ssn Francisco, 1966. ( 5 ) Wnrm. E. H.. CXEN,M. C., AND DOGAT.L. A,, J . Ovg. Cham.. 31, 3038 (1966). ( 6 ) Cxow, Y. L.. TAM,N. 8.. *an LBE. A. C. H.. Con. J . Chem.. 4 7 , 2441 (1969) and referenoeatherein. ( 7 ) Mosa. R. A,, TslrahedronLctt.. [71.711 (1966). ( 8 ) BARTON, D. H . R., Pure Appl. Cham., 16.1 (1988). ~ N G., . *AD DYCKWORTH, A. C., J. Amer. (9) KUHN,L. P., K L & I N B P E G. Chem.Soc.,89,3858 (1967). J. B . F. N.. AND . D BOER.TR.J. Tcbo(10) D n a a ~E. ~ ,E . J., ENOBERTB, hcdronLel1.. (311,2651 (19691. (111 Eowmns, O.E.. AND ROBICH, R. 8.. Con. J . Chcm..45,1287 (1967). , 1138 (1970). (121 Cn0w.Y. L.. AND TAM.J. N. S.. J . C h m ~ S o c .(C). (13) E I S T E N TB.. , RBBITS.M., HECX.G . , A N D SCHW*LL, H.. Houhen Wsvl: "Methoden Dsr Organiaohen Chemie," ( E d i l o ~ : Mdmen.. E a a m ) , Vol.10. part 4. Georg Thieme Verlag. Stuttgart. 1968, D. 473. E. H.. AND AUPOEBMARBA.C. A.. JI.. J . A m w . chem. soo., (14) WHITE, 83,1174,1179 (1961). (15) S ~ n s m w r s s mA., , Jr.. A N D S o ~ n n r ~ W ~ .n D., . J . Amer. Chcm. Soc.. 7 9 , 2888 (1957). (16) WXITE, E. H., A N D E L L I ~ S AC. , A.. J . Amar. Chcm. Soc.. 89, 165 (19671. D. W., J . Amm. Cham. Soo., 91, 7539 (1969). (17) Moss, R. A., AND REOER, (18) Moss. R.A,. AND S c n n b r ~ wF. , C.. Tctrohcdron.24,2881 (1968). (I91 Moss. R.A.. AND LANE, S. M., J . A m s . Cham. Soe.. 89, 5655 (19671. (20) Moss, R. A,, R~r3.n. D. w., *.wn EMERY, E. M . . J . Amer. Cham. soc.. 9 2 , 1366 (19701. (21) NEWMAN,M. S., AWD BEARD.C. D.. J . A m y . Cham. SOC..9 1 , 5677 (19691, and referenoesththerein. M. 6.. A N D KUTNER.A,. J . Amer. Chcm. Soc.. 7 3 , 4199 (22) NEWMAN.
. Y.. K*aa~armea,J. A,, A N D O'CONNOB.B. R., J . Amer.
c., 8 7 , 863 (1965). (241 TXORNTON, R., Ph.D. Thesis. The Johns Hopkina Univeraity. Baltimore, Maryland, 1907. 1251 . ~.Humoen. R.. AND RircxAnoT. C.. Ann. Chem.. 601. 1. 21 11956) . . (261 R ~ C H & T . c.. M ~ Y E.. , ' ~ n i u n m s s n a .B . . OPBENORTR. H.-J.. TAN, C. C.. AND VBRNER.R.,in"Eaaaya onFree RadicalChernistry," Special Puhlioation No. 24. The Chemical Sooiety. Burlington House London. 1970.Ch. 3. (271 Cadoghn, J. I . G.. reference (26). Ch.4. (28) C m o a ~J.~ I.. G., Account Chem. Rca.. 4 , 186 (1971) 1291 B~ ~ u,r a ~ n,~~ R. ~m J..,~ ~J.. CHEM. E ~ ~ 0 . . 4 3 . 3 9 11966). 8 , ~(30) MmNwaLn. J.. A N D Wnemsn. T . ~N..>. A&. cham. Sac., 92, 1009 ~
~
~
~
(60). Summary
Recent work with nitrosoamides has provided the modern chemist with mechanistic insights into the reactions of interesting compounds as well as the synthetic routes to them. The photochemistry of nitrosoamides provides a method for the selective fnnctionalieation of a remote site in addition to the production of nitrogen radicals for mechanistic and theoretical studies. Base catalyzed decomposition of nitrosoamides offer unique methods for generation of the diaeohydroxide and the diazoester intermediates of the nitrous acid and the nitrosamide deaminations. In addition to deamination, diazotates are useful in the synthesis of vinyl cations and vinyl derivatives. The thermal decomposition of aliphatic nitrosoamides offers a synthetically important and stereospecific method for the deamination of aliphatic amines. Modifications of nitrosoamides allow the chemist to "fine tune" the compound's characteristics so that more sophisticated studies can be carried out. These 734 / Journal o f Chemical Education
~. . , .. .. .., . ., ...,...., (34) UBKo a o v d , M.. Gn~zwmbex,J., A N D H m o m a o n . T., J . Amer. Chem. So&, 9 2 , 203 (1970). (35) KEANA,J. B. W., AND KIM,C. U., J . Om. Chem.,36,118 (1971). (36) NOIIAND. W. E.. COOLET.J. H., A N D MCVEIRX.P. A,. J. Amcr. Chsm.
.".,--,lnOC1 ,10
