Highly efficient Friedel-Crafts-type benzylation via benzyl cations generated in multiple spacer-molecule separated ion-pairs

Article abstract of DOI:10.1039/b312664a

Deamination, as a facile route to highly reactive carbocations, is of interest to several areas of organic chemistry, industry, and medicine. The reactivity and utility of these carbocations derives from the presence of a lone nitrogenous entity (N₂or N₂O) interposed between the ion-pair. We report here the synthesis of a new deamination precursor whose nitrosation and subsequent decomposition constitutes a novel deamination method. In this novel approach, multiple spacer-molecules are generated in the inter-ion space. The resultant cations are exceedingly reactive but are longer-lived than carbocations derived from standard deaminations. The result is nearly quantitative yields of solvent-derived products from even poorly nucleophilic solvents such as benzene, toluene, and mesitylene.

Full text of DOI:10.1039/b312664a

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Highly efficient Friedel–Crafts-type benzylation via benzyl cations
generated in multiple spacer-molecule separated ion-pairs†
Ron W. Darbeau,* Gregory A. Trahan and Luis M. Siso
Department of Chemistry, McNeese State University, Lake Charles, Louisiana, 70609, USA.
E-mail: rdarbeau@mail.mcneese.edu
Received 10th October 2003, Accepted 15th December 2003
First published as an Advance Article on the web 27th January 2004
Deamination, as a facile route to highly reactive carbocations, is of interest to several areas of organic chemistry,
industry, and medicine. The reactivity and utility of these carbocations derives from the presence of a lone
nitrogenous entity (N2 or N2O) interposed between the ion-pair. We report here the synthesis of a new deamination
precursor whose nitrosation and subsequent decomposition constitutes a novel deamination method. In this novel
approach, multiple spacer-molecules are generated in the inter-ion space. The resultant cations are exceedingly
reactive but are longer-lived than carbocations derived from standard deaminations. The result is nearly quantitative
yields of solvent-derived products from even poorly nucleophilic solvents such as benzene, toluene, and mesitylene.
formation is relevant because these species are believed to (1)
Introduction
serve as inert “spacer molecules” between the gegenions, (2)
The standard Friedel–Crafts (F–C) alkylation of aromatic
exert an enthalpic pull on the forward reaction as a result of
compounds is a Brønsted or Lewis acid-catalyzed reaction of
their inherent stability, (3) exert an entropic pull on the forward
an aromatic substrate with alkyl halides, alkyl esters of strong
reaction, and (4) essentially negate the likelihood of a reverse
acids, with alcohols, or with unsaturated compounds. This
reaction because their mobility and ease of escape from the
versatile reaction has wide synthetic use and its mechanism
solvent cage makes them unlikely to remain in a favorable
continues to be the subject of lively debate.2,3b The central
mechanistic questions surrounding the F–C reaction deal with
the identity of the electrophile, the kinetics of the formation
of the arene–electrophile σ-bond, the presence of defined
and directed intermediates preceding the arenium ion and the
source of the meta isomer.
Darbeau et al. have utilized deamination chemistry as a
means of elucidating the details of the bond-forming step of
geometry for recombination.
When the carbocation e.g., the benzyl cation, is stabilized and
devoid of β-hydrogens, SN1-type reaction with the counterion
or the solvent is its only fate.3,5–7 Cation–solvent reactions are
believed to occur prior to diffusion of the nitrogenous entity
from between the ions in the solvent cage since the latter process
is thought to lead to essentially instantaneous internal collapse
of the ion-pair to give the corresponding ester.4a Thus, the
the F–C reaction as well as in tracing the origin of the mech-
nitrogenous entity is implicated in the partitioning of the carbo-
anistically important meta isomer.3b These deaminative F–C
alkylations involved the generation of poorly complexed
phenylcarbenium ions (benzyl cations) in equimolar benzene/
toluene mixtures via thermolyses of N-4-R-benzyl-N-nitroso-
cation between its nascent counterion and the medium; the
longer it remains in the pocket between the ions, the more
opportunity is afforded the carbocation to interact with the
medium.3–7 If the reactivities of the carbocation and solvent
amides and via N-4-R-benzyl-N-nitroso-O-acylhydroxylamines.
have reached some threshold level for reaction,9a then such
Deamination generates highly reactive carbocations as part
extended carbocation–solvent interaction could lead to
of a nitrogenous entity separated ion-pair [NESIP; eqn. (1)].3–7
enhanced yields of products derived from the solvent.
Their high reactivity3–7 arises from the low activation energy
required for the loss of N2 (or N2O) from the alkyldiazonium
Solvent-derived products from deamination
(or related) precursor allowing the cation to be formed with
minimal solvent participation.3–7 Additionally, the temporary
The yield of solvent-derived products (SDPs) increases with the
reactivity of the cation,3c with the mole fraction and nucleo-
screening of the cation from its counterion by the sheer physical
philicity of the active solvent,3c and in an inverse manner with
presence of the nitrogenous entity results in the maximal
the nucleophilicity of the counterion.3c The yield of SDP also
generally rises, but to a lesser extent, with decreasing temper-
ature3c and when the nitrogenous molecule = N2O rather
than N2.3c The latter observation relates to the present work
(vide infra) and is believed to arise from greater shielding of the
cation from the counterion by the more massive N2O and a
more lethargic departure by this heavier molecule9c allowing the
cation more opportunity to interact with the solvent.3
positive charge at the electron-deficient center.3a,b,8
(1)
The utility of deamination
Because the reaction occurs in solution, the nascent nitro-
genous entities between the ions are not gases upon generation.
They form gases, however, when very large numbers of their
molecules gather upon escape from the various solvent cages in
which the unimolecular thermolyses occur. Nitrogenous entity
Deamination is a useful method of preparation for products
of industrial (e.g. high-melting polystyrene),5 synthetic (e.g.
monoalkylated heteroaromatics,3d mixed diacylamines,3e,6 and
stable onium ion salts),3e,4b,6 and medicinal (e.g. cancer chemo-
therapeutic agents)7c importance.3,5,6,7c The technology has also
been applied successfully to physical organic studies including
examination of the bond-forming step of the Friedel–Crafts
† Hyperdeamination chemistry. Part 1.1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
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Scheme 1 Potential decomposition pathways for N-nitroso-N-carbobenzoxy-O-carbobenzoxyhydroxylamine showing two phases of ion-pair
collapse.
reaction,3a,b the Brown Selectivity Relationship,3a,b to the novel
N-nitrosoamide-mediated Ritter-type reaction,6b,c and most
recently, to the postulation of new subclasses of steric, orbital,
and electronic effects.7d
The utility of deamination arises from the ability of the
highly reactive carbocations to be scavenged by solvents poss-
essing π- and/or n-electron pairs. Such carbocation–solvent
interactions are limited partially8a by the lifetime of the carbo-
cation.3–7 Presumably, if the carbocation’s lifetime is extended
by delaying internal collapse, then carbocation–solvent inter-
action would proceed for longer leading to more SDPs and
enhancement of deaminative technology. Further, since the
shielding of the cation from its gegenion increases through
generation of the bulkier, heavier N2O vs. N2 (vide supra)3c,10b
then, if more than one spacer molecule is generated between the
ions, they should collectively provide better inter-ion shielding
presumably due to the greater volume occupied by the spacer
molecules and the increased inter-ion distance, among other
factors.9d More time would be needed for diffusion of multiple
spacer molecules from between the ions resulting in enhanced
opportunity for carbocation–solvent interaction (= larger yields
of SDPs). Thus a “multi-spacer” deamination (“hyperdeamin-
ation”) would be of special use where the intent is derivatization
of relatively inert solvents.
We report here the synthesis of the deaminative precursor:
N-carbobenzoxy-O-carbobenzoxyhydroxylamine (1).10a,b This
compound was chosen because it should be readily N-nitro-
sated (by “NOϩ”, N2O4, or nitrosyl halides, etc.) to derive its
N-nitroso-derivative (2). The species 2 is structurally compar-
able to both N-nitrosoamides (6) and N-nitroso-O-acylhydroxyl-
amines (7) and could potentially decompose along either, or
both, deaminative pathways. However, the greater lability of
N-nitroso-O-acylhydroxylamines (these compounds spontan-
eously deaminate even at Ϫ100 ЊC)3c over N-nitrosoamides
(some of which have half-lives on the order of months at
25 ЊC)3c suggests that the activation energy for decompositions
of the former is much lower. Consequently, decomposition was
expected to occur as in Scheme 1.
SDP = diphenylmethane (DPM; from reaction in benzene),
the isomeric methyldiphenylmethanes (MeDPMs; from reac-
tion in toluene), of benzylated mesitylene (BM; from reaction
1
in mesitylene) was determined by H NMR spectroscopy by
examining the signals for the benzylic methylene groups. The
presence of Phase I and Phase II products [Scheme 1; dibenzyl
carbonate (4) and dibenzyl ether (5), respectively] from internal
collapse were determined in like manner.
N-Carbobenzoxy-O-carbobenzoxyhydroxylamine (1) was
prepared by treatment of N-carbobenzoxyhydroxylamine12a
(NCH) with 1.1 equivalents of benzyl chloroformate (BCF)
in methylene chloride in the presence of vacuum-dried
NaHCO3.11 NCH, itself was prepared from the reaction of
hydroxylamine and 1.2 equivalents of BCF in CH2Cl2 with
NaHCO3 present, as above. Solutions of recrystallized (ether/
hexane) 1 in each of the anhydrous arenes were treated with
Ϫ
∼0.5 equivalents of NOϩSbF6 under argon at 21 ЊC; the
reactions were quenched after 75 minutes of vigorous agitation
12b
by washing with saturated NaHCO3(aq). The products of the
reactions (Table 1) are those from internal collapse (vide supra,
Scheme 1): 4 (δ 4.79–5.06),12c and 5 (δ 4.31–4.81);12c the SDPs
from the arenes are DPM (δ 3.72), MeDPMs (δ 3.74), and BM
(δ 3.84).
The data (Table 1) show the product distributions from
thermolysis of N-benzyl-N-nitrosopivalamide (6a; nitrogenous
entity = N2), nitrosation of N-benzyl-O-benzoylhydroxyl-
amine [7; spacer molecule (= nitrogenous entity) = N2O],3h and
N-carbobenzoxy-N-nitroso-O-carbobenzoxyhydroxylamine [2;
spacer molecules = N2O ϩ nCO2; n = 1 or 2 (vide supra)]. The
relatively small disparity in the yields of SDP between the
deaminations of 6a and 7 has been accounted for in terms of
The formation and decomposition of 2 were performed in
benzene-d6, toluene-d8, and mesitylene-d12. The presence of
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
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Table 1 Yielda of solvent-derived product from deaminative and hyperdeaminative benzylation of selected arenes
% Solvent-derived product
Precursor
Deamination mode
Temp (ЊC)b
Spacer molecule(s)
Benzene
Toluene
Mesitylene
6ac
7d
normal
normal
hyper
20
25
21
N2
N2O
N2O ϩ nCO2
7.5
8.4
98.7
16.3
21.6
99.5
28.2
99.6
2e
f
a Data are averages of at least duplicate runs. % SDP ϩ % ion pair collapse is taken as = 100% (trace unknowns 2%, in some runs). b Although the
yield (std. dev. 0.3) of solvent-derived product falls with decreasing temperature (ref 3c), the change is small and is not likely to be expressed over a
5 degree range. c N-Benzyl-N-nitrosopivalamide was used. d N-Benzyl-N-nitroso-O-benzoylhydroxylamine was used. e N-Carbobenzoxy-N-nitroso-
O-carbobenzoxyhydroxylamine was used. f One and or two CO2 molecules are generated here.
the greater spatial and temporal shielding of the benzyl cation
from its gegenion by the larger, heavier N2O vs. N2.3a–c,h,10c
The huge difference in hydrocarbon yield between the hyper-
deaminative and the standard deaminative cases (even with
N2O rather than N2 as the spacer molecule) is staggering. The
enhanced yield of SDP suggests that (1) the hyperdeaminatively
generated benzyl cation is far more reactive than its deamin-
ative counterpart1 and/or (2) the cation is longer-lived and has
more time for solvent–cation interaction leading to SDP. Both
of these hyperdeaminative properties arguably arise from
greater shielding of the cation from its nascent counterion.
Thus, we propose that the presence of these multiple spacer
molecules reduces the stabilizing cation/counterion ionic inter-
action resulting in the essentially uncomplexed, highly reactive
species observed.1
Additionally, the greater cation/counterion shielding by the
multiple spacer molecules in the inter-ion space militates
against cation/counterion approach within bonding distance. In
this way, the spacer molecules impose significant steric hin-
drance to ion-pair collapse. The cumulative result then is the
formation of highly uncomplexed cations that are afforded
extended time for cation–solvent interaction resulting in the
enhanced yields of SDP observed. It should be noted that the
intuitive concept regarding the reactivity of an intermediate
requires that highly reactive species should exist for a short
time. It would appear that in the hyperdeaminative case this
inverse relationship between the cation’s reactivity1 and lifetime
may not hold.
Table 1 shows that in the deaminative series via the nitrosoa-
mide, there is a 117% increase in SDP on going from benzene to
the more nucleophilic toluene. The yield of SDP increases by a
further 73% when the reactions are performed in mesitylene
rather than toluene. The implication therefore is that the deamin-
atively generated cations are able to discern between solvents
of differing nucleophilicity. However, in the hyperdeaminative
case, there is less than a 1% change in % SDP as the solvent is
varied from benzene to toluene to mesitylene indicating that
the hyperdeaminatively generated carbocations are essentially
incapable of distinguishing between the nucleophilicities of
these three solvents. It would appear then that the hyper-
deaminatively-generated cation’s lifetime/reactivity imposes a
leveling effect on the solvent nucleophilicity.
studies, the counterions are sulfonates and the solvent is either
an aqueous alcohol or aqueous acetonitrile.13d In these scen-
arios, extremely high yields of SDP must occur for the follow-
ing reasons (1) the extremely poorly nucleophilic sulfonates do
not efficiently compete against the nucleophilic solvent for the
capture of the carbenium ions, consequently, (2) the nucleo-
philic solvent almost completely captures the carbocation. Fur-
ther, (3) although some carbocations may collapse into the
sulfonates, this reaction produces the very labile benzyl sulfon-
ate esters which in the presence of the highly polar (and nucleo-
philic) solvent systems employed by Maskill13 are strongly
predicated to subsequent SN phenomena to yield even more
SDP. The net result is that in the Maskill system it is not surpris-
ing that extremely high yields of SDP are observed because
solvent alkylation stems from the presence of an aggressive
solvent capturing both first and second generation benzyl
electrophiles.
The Maskill studies13a–c are mentioned here because they
bear a tangential similarity to the present work. However, they
do not directly compare to the present work because in our
studies the counterions are the much more nucleophilic carbo-
nates and/or alkoxide and the cations are generated in solvents
of comparatively very low nucleophilicity and polarity. Con-
sequently, efficient and irreversible trapping of the cations by
the counterions might be expected to occur in our system lead-
ing to low yields of SDP (indeed in N-nitrosoamide thermo-
lyses in benzene, this is the case). Yet, in the present study not
only is the yield of SDP high, it is nearly quantitative. Without
the advantages of the Maskill system, therefore, a new explan-
ation must be found for the tremendous yield enhancement
observed.
The central thrust of this report is that the carbocation
generated here is so well shielded (physically = spatially and
temporally)9d from its counterion that it is almost completely
constrained against interacting with it and therefore to near
specificity in its reactions with even poorly nucleophilic sol-
vents. This is a marked change in behavior from the N2- and
N2O-separated ion pairs where even though N2O provides
better shielding and escapes more slowly from the inter-ion
space than N2, the change in %SDP is much smaller than
observed between the hyperdeaminative and deaminative cases.
(Table 1).
Based upon N-nitrosoamide decomposition in acetic acid,4c
methanol,3h and pyrrole,3d we have previously argued that a
minimum of 20% of carbocations in NESIPs are committed to
internal collapse with their nascent counterions.3d This com-
mitment to ion-pair collapse is evidently absent in the hyper-
deaminative case due to the electronic shielding and steric
hindrance imposed by multiple spacer molecules between the
ion-pair.
The near quantitative alkylation of solvent by hyperdeamin-
ative-generated benzyl cations as reported here is not unique
and has been reported by other workers such as Maskill et
al.13a–c Indeed in the Maskill cases13a–c very large yields of
solvent-derived products (SDP) arise from the generation of
such cations in appropriate aqueous solvents. However, in those
Internal collapse products from hyperdeamination
Although the mechanistic details of the reaction are yet to be
fully elucidated, the product distribution and analogies to the
established chemistry of N-alkyl-N-nitroso-O-acylhydroxyl-
amines suggest the following sequence of events. The decom-
position of 2 evidently occurs by fragmentation of the labile
N–O hydroxylamino bond to generate the intimate ion pair 3a.
Dediazoniation of 3a yields an N2O-separated ion pair 3b, the
carboxylium ion of which undergoes cationic decarboxylation
to derive a double-spacer molecule separated ion pair 3c. It is to
be expected that fission of the carboxylium ion would be facile
because of resonance stabilization in the benzyl cation and
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
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Table 2 Product distributiona from hyperdeaminative benzylationb of
selected arenes at 21 ЊC
be subject to nitrosations leading to side products or labile
intermediates13d that would complicate the reaction.
% Internal collapse products
% Solvent-derived
Conclusion
Solvent
product
Phase I
Phase II
We have presented evidence of a facile, novel deaminative
method. This “hyperdeaminative” mode evidently generates
carbocations that are longer-lived and perhaps even more
reactive than those generated via standard deamination.1
At this point we cannot state whether the spacer molecules
have a greater effect on cation lifetime or inherent reactivity,
however, it is clear that the confluence of enhanced lifetime/
reactivity results in extremely efficient solvent capture of
even poorly nucleophilic arenes. The technique would appear
to be ideal for derivatization of solvents of low nucleo-
philicity. Evidently the enhanced lifetime/reactivity of the
hyperdeaminatively generated carbocations derives from the
electronic insulation of the carbocation from the stabilizing
effects of its native counterion, from severe steric hindrance
to ion-pair collapse, and from increased opportunity for
carbocation/solvent interaction.
Benzene
Toluene
Mesitylene
98.7
99.5
99.6
1.2
0.5
0.4
trace
0.0
0.0
a Data are averages of at least triplicate runs (std. dev. 0.3). % SDP ϩ %
ion pair collapse is taken as = 100% (trace unknowns 2%, in some runs).
b N-carbobenzoxy-N-nitroso-O-carbobenzoxyhydroxylamine was used.
because CO2 formation is both enthalpically and entropically
favored. The carbocation in 3c has the options of reacting with
solvent and collapsing with the alkyl carbonate ion to form
dibenzyl carbonate 4 (Phase I ion-pair collapse; Scheme 1).
Some alkyl carbonate ions that avoid capture by the first gener-
ation cation undergo anionic decarboxylation to generate the
triple molecule separated ion pair, 3d. This fission converts the
poorly basic alkyl carbonate anion into the strongly basic
alkoxide, but probably progresses largely due to the negative
enthalpy and positive entropy changes associated with CO2
formation.14a Nonetheless, it is to be expected that this second
decarboxylation is somewhat less facile than the former. The
second generation cation in 3d may undergo Phase II ion-pair
collapse into dibenzyl ether, 5 or may react with solvent to form
SDP. The relative yields of SDP and Phase I and Phase II
products (Scheme 1) are shown Table 2.
The larger yield of 4 vs. 5 may indicate that (1) 3c is more
abundant than 3d implying that the anionic decarboxylation is
slow relative to ion-pair collapse of 3c. Alternatively, (2) ion-
pair collapse in 3d may be prohibitively slow relative to collapse
in 3c due ostensibly to greater inter-ion shielding in the latter. It
would appear that benzylation of the solvent occurs via two
hierarchies of highly reactive benzyl electrophiles with the
second generation being exceedingly reactive. Quantification of
the roles of each generation of benzyl electrophile in solvent
derivatization is currently being investigated in our laboratory.
Experimental
Materials and methods
All commercially available reagents were reagent grade and
were used without further purification. All moisture sensitive
experiments were performed in a glovebox, which had been
purged exhaustively with ultra high purity argon. Chemical
1
shifts in the H NMR spectra are reported in ppm downfield
from internal TMS. Spectra were obtained on JEOL Eclipseϩ
300 MHz FT-NMR, Perkin Elmer 1600 Series FT-IR and
Beckman Model 25 UV-Vis. All syntheses and reactions
of N-nitrosoamides were performed in the dark; in many
instances, reactions were performed in evacuated sealed NMR
tubes. Elemental analyses were performed by Quantitative
Technologies Inc.
Handling and storage of N-benzyl-N-nitrosopivalamide (NBNP)
N-Nitrosoamides are thermolabile, photolabile, and unstable in
the presence of acids, bases, and moisture, therefore they are
stored in dry vials under an inert gas, and in a cryogen dewar
containing liquid nitrogen. NBNP must be stored and handled
in the dark. Caution! Nitrosoamides should be handled with
extreme care due to their possible mutagenicity15a and carcino-
genicity (local and systemic).15b Efficient fume hoods and
appropriate personal protective equipment (chemical resistant
gloves, safety glasses, lab coat, etc.) should be used when hand-
ling these types of compounds.
Nitrosation of N-carbobenzoxy-O-carbobenzoxyhydroxylamine
(1) in hexane
Compound 1 was nitrosated via NOSbF6 in hexane-d14 with
vigorous agitation. Decomposition of the nitroso-derivative (2)
in an inert solvent excludes the pathway leading to SDP, con-
sequently the only fate available to the carbocation is the rel-
atively slow ion pair collapse. This decomposition in an inert
medium allows for the determination of the relative amounts of
Phase I and II ion-pair involvement in product formation. The
data show the formation of 83% dibenzyl carbonate (6) and
17% dibenzyl ether (7). This result is significant, because it indi-
cates that the initial cationic decarboxylation, which leads to
the Phase I separated ion pair (Scheme 1), is more facile than
the subsequent anionic decarboxylation, which leads to Phase
II separated gegenions (Scheme 1).14b Also these results mean
that all of the data from the decompositions in the arenes (vide
supra) are weighted averages, of the double- and triple-spacer
molecule separated ion-pairs.
It should be pointed out here that under ideal circumstances,
parallel reactions in solvents of varying bulk properties (e.g.,
polarity, hydrogen-bonding ability, etc.) would have been con-
ducted to determine whether the 83 : 17 apportioning of reac-
tions via Phase I/Phase II ion-pairs was solvent dependent.
Unfortunately, the choice of solvent for this investigation was
severely limited because polar solvents would possess n-pairs of
electrons and since the carbocations are able to intercept the
reluctant π electrons of benzene, they would be expected to
interact with the n- and π-containing systems of haloalkanes,
alcohols, carbonyls, etc. Further, nucleophilic solvents may also
N-Carbobenzoxyhydroxylamine (NCH)
This compound was prepared by free-basing the hydroxylamine
hydrochloride salt with an excess of sodium bicarbonate in
100 ml of methylene chloride, with vigorous stirring for
∼15 minutes. Then 1.2 eq. of benzyl chloroformate (BCF) was
added to the reaction vessel and allowed to react overnight at
room temperature. After 24 hours the solution was vacuum
filtered to remove the sodium bicarbonate. The bulk solvent
was removed by rotary evaporation, and then the solution was
taken to complete dryness using a high vacuum pump. The
solid residue consisted of the monocarbobenzoxylated hydroxy-
lamine, N-carbobenzoxy hydroxylamine (NCH). The NCH was
then recrystallized using ether and hexane. NCH is hydrolyz-
able, the dry neutral solid is stored under N2: mp 62–64 ЊC
(lit: 65–70).16a IR (KBr) 3373, 3300, 1703, 1502, 1398, 1288,
1
1119 cmϪ1; H NMR (CDCl3) δ 5.19 (s, 2H), 5.89 (s, 1H), 7.21
(s, 1H), 7.36 (s, 5H). Anal. Calcd for C8H9NO2: C, 57.5; H, 5.4;
N, 8.4; O, 28.7. Found: C, 57.8; H, 5.4; N, 8.3; O, 28.4%.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
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N-Carbobenzoxy-O-carbobenzoxyhydroxylamine (1)
isolation were performed in the dark: IR (neat) 1720, 1605,
1502, 1390, 1375 cmϪ1; 1H NMR (CD3CN) δ 1.45 (s, 9H), 4.97
(s, 2H), 7.05–7.40 (m, 5H); UV (CH2Cl2) λmax 275 nm
(ε = 500), 400 nm (ε = 63) 394 nm (sh), 422 nm (ε = 66).
The purified NCH was then redissolved in methylene chloride
and an excess of sodium bicarbonate, and 1.1 eq. of BCF were
added. The reaction was left stirring at room temperature over-
night. The solution was then filtered, solvent was removed, and
1 was recrystallized using the procedure described. Compound
1 is hydrolyzable and therefore should be stored in a sealed
container, under an inert gas (nitrogen or argon), and placed in
a desiccator: mp 72–74 ЊC. IR (KBr) 3221, 1805, 1716, 1506,
1244, 1146 cmϪ1; 1H NMR (CDCl3) δ 5.23 (s, 2H), 5.26 (s, 2H),
7.35 (s, 10H), 7.88 (s, 1H). Anal. Calcd for C18H15NO5: C, 63.8;
H, 5.0; N, 4.6; O, 26.6. Found: C, 63.7; H, 4.9; N, 4.6; O, 26.4%.
Decomposition of N-benzyl-N-nitrosopivalamide
The seals to the solvent containers, benzene-d6, toluene-d8, and
mesitylene-d12, were opened in the glove box. The solvent was
then dried over sodium sulfate for 30 minutes in order to
remove trace moisture. 1.5 ml of the appropriate solvent
was then pipetted into 5 ml pressure vials. 100 µL of NBNP
were pipetted into the pressure vials and allowed to decompose
at 21 ЊC for 48 h (10 half-lives). A sample of the NBNP
was analyzed via FT-NMR in order to establish a baseline
percent decomposition, which was used to correct the percent
solvent derived product and percent ion collapse product. All
decompositions were performed in triplicate.
Nitrosation and decomposition of compound 1
The nitrosation of compound 1 was performed under an inert
argon atmosphere in a glove box. Due to the highly hygroscopic
nature of the nitrosating agent, precautions were taken to mini-
mize the likelihood of corrupting the dry inert environment.
Prior to the introduction of any glassware into the glove box,
the glassware was vacuum dried overnight at 80 ЊC. Approx-
imately 23 mg of 1 were placed into labeled individual 16 ml
teflon-lined screw top vials. The samples were vacuum-dried
overnight.
N-Benzyl-O-benzoylhydroxylamine (7)
This was prepared by the method of Zinner.16d IR (CH3Cl) 1725
cmϪ1; 1H NMR (CDCl3) δ 4.28 (s, 2H), 7.29–7.97 (m, 9H), 7.98
(d, 2H, J = 12 Hz).
Decomposition of N-benzyl-O-benzoylhydroxylamine (7)
This was performed as outlined in Ref. 3c.
The solvent containers, benzene-d6, toluene-d8, and mesityl-
ene-d12, were opened in the glove box. The solvents were then
dried over sodium sulfate for 30 minutes. 1.5 ml of the appro-
priate solvent was then pipetted into each of the screw top vials
containing the samples of 1. The vials were then shaken until all
of 1 had dissolved, forming a ∼0.05 M solution. Approximately
10.2 mg of nitrosonium hexafluoroantimonate (NOSbF6) was
weighed out into a labeled screw top vial; the 0.05 M solution
of 1 was then pipetted into the vial containing the NOSbF6.
Upon addition of the solutions of benzene-d6, toluene-d5, and
mesitylene-d12, the solutions changed from colorless to pale
yellow, deep yellow, and orange/rust color, respectively. The
vials were sealed and removed from the glove box and agitated
vigorously on a multiple wrist shaker for 75 minutes at 21 ЊC.
The solutions were quenched using a saturated sodium bicarb-
onate solution, in order to neutralize any unreacted NOSbF6.
The organic layer was then collected, sealed in a screw top
vial, placed in a desiccator, and refrigerated at Ϫ20 ЊC until
the analysis could be performed. Chloroform-d extractions
Analysis of decompositions
The percent solvent derived products (SDPs) and percent ion
collapse products (ICPs) were determined using 1H NMR
spectroscopy by integrating the benzylic signals of starting
materials and of the products. The values given for % SDP and
% ICP are averages of a least three replicants, and three sets of
integration values per run.
Acknowledgements
Acknowledgement is made to the Louisiana Education Quality
Support Fund, Grant # LEQSF-(2001-04)-RD-A23, adminis-
tered by the Louisiana Board of Regents, the Calcasieu Parish
Industrial and Development Board Endowed Professorship
administered by the McNeese State University Foundation,
the Shearman Research Initiative administered by the Office of
Research Services, MSU, and to the Chemistry Department,
MSU for partial support of this research. The authors also wish
to acknowledge the contributions of Mrs. Nyla R. Darbeau
and Ms. Joan E. Vallee.
1
were performed on the aqueous samples and analyzed via H
NMR to insure that no reaction products were present. All
decompositions were run in triplicate.
N-Benzylpivalamide
N-Benzylpivalamide was prepared from the method of Heyns
and von Bebenburg:16b mp 81–82 ЊC (lit16c mp 81–82 ЊC); IR
References and notes
1
(KBr) 3309, 1689, 1510, 1390, 1375 cmϪ1; H NMR (CDCl3)
1 R. W. Darbeau, L. M. Siso, G. A. Trahan and R. S. Nolan,
submitted to Org. Biomol. Chem. [B401060D].
δ1.27 (s, 9H), 4.44 (d, 2H, J = 7 Hz), 5.90 (bs, 1H), 7.26–7.32
(m, 5H); UV (Et2O) λmax = 284 nm (ε = 209).
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N-Benzyl-N-nitrosopivalamide (NBNP)
A mixture of N-benzylpivalamide (9.5 g, 50 mmol), NaOAc
(25 g, 0.3 mol) and Na2SO4 (50 g) was dried at oil pump
vacuum. Chloroform (300 cm3) freshly distilled from P2O5, was
added to the solid material (under N2) and the suspension was
cooled to Ϫ78 ЊC. A solution of N2O4 (l) (20 cm3, 0.31 mol) in
CHCl3 (100 cm3) at Ϫ78 ЊC was then added to the stirred sus-
pension at Ϫ78 ЊC which was then allowed to warm to Ϫ25 ЊC
over 10 min. After a further 15 min at Ϫ25 ЊC, the suspension
was evaporated in vacuo for ∼15 min until a lemon yellow color
was observed. Ether at Ϫ20 ЊC was then added and the suspen-
sion was washed in turn with saturated solutions of NaCl,
Na2CO3 and NaCl at Ϫ5 ЊC. The organic phase was dried over
Na2SO4 at Ϫ30 ЊC then evaporated in vacuo (at Ϫ30 ЊC) to yield
11 g (50 mmol, 100%) of a lemon yellow oil. The synthesis and
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
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66, 2681; (h) R. W. Darbeau, Ph.D. Thesis, The Johns Hopkins
University, Baltimore, MD, 1996.
9 (a) For example, the deaminatively-generated benzyl cation is
without action on methylene chloride but the 1-norbornyl cation
9b
generated via deamination abstracts chloride from CH2Cl2
;
(b) E. H. White, R. H. McGirk, C. A. Aufdermarsh, Jr., H. P. Tiwari
and M. J. Todd, J. Am. Chem. Soc., 1973, 95, 8107; (c) It is unclear
whether the greater volume or lower volatility of N2O vs. N2 is the
major operating factor. Indeed, other factors such as the polarity,
polarizability, etc. may also be important. For example, diffusion of
the polar N2O through the non- polar “skin” of the solvent cage (in
a non-polar solvent) may be less facile than the similar departure
of N2; (d ) The physical shielding of the cation from the nascent
counterion probably possesses a spatial component in that the
multiple NEs keep the ions at an enhanced distance apart from each
other. Since it would presumably take a longer time for the multiple
NEs to diffuse from the inter-ion space, then the shielding possesses
a time-based component as well.
10 (a) E. Boyland and R. Nery, J. Chem. Soc. (C), 1966, 354;
(b) A deaminative precursor may be loosely defined as any species
that upon activation (thermal, photolytic, chemical, enzymatic,
or otherwise) undergoes deamination.; (c) The molecular diameters
of N2 and N2O are 3.681 and 3.879 Å, respectively ( R. B. Bird,
W. E. Stewart, E. N. Lightfoot, in Transport Phenomena
Wiley: Chichester, UK, 1960; p 744);. The molecular volumes
(VM) were calculated using VM = (4/3)πr3, VM(N2) ≈ 26.1 Å and
VM(N2O) ≈ 30.6 Å. Thus N2O is ∼17% larger than N2; it is also 57%
heavier.
4 (a) E. H. White, K. W. Field, W. H. Hendrickson, P. Dzadzic,
D. F. Roswell, S. Paik and P. W. Mullen, J. Am. Chem. Soc., 1992,
114, 8023; (b) E. H. White, J. T. DePinto, A. J. Polito, I. Bauer and
D. F. Roswell, J. Am. Chem. Soc., 1988, 110, 3708.
5 R. W. Darbeau, M. S. Delaney, U. Ramelow and K. R. James,
Org. Lett., 1999, 1, 796.
6 (a) R. E. Gibble, M. S. Thesis, McNeese State University, 2001;
(b) R. W. Darbeau, R. E. Gibble and R. S. Pease, J. Chem. Soc.,
Perkin Trans. 2, 2001, 1084.
7 (a) R. W. Darbeau, R. S. Pease and R. E. Gibble, J. Org. Chem.,
2001, 66, 5027; (b) R. W. Darbeau, E. V. Perez, J. I. Sobieski, W. A.
Rose, M. C. Yates, B. J. Boese and N. R. Darbeau, J. Org. Chem.,
2001, 66, 5679; (c) R. W. Darbeau, Recent Res. Dev. Org. Chem.,
2001, 5, 107; (d ) R. W. Darbeau, R. S. Pease, E. V. Perez, R. E.
Gibble, F. Ayo and A. W. Sweeney, J. Chem. Soc., Perkin Trans. 2,
2002, 2156.
8 (a) Extensive work on carbenium ion lifetime and solvent and/or
nucleophile interaction have shown that in the presence of very
strong nucleophiles such as azide, combination with carbenium ions
are diffusion controlled.8b–e With poorer nucleophiles the rates of
reaction depend upon the reactivities of both cation and nucleophile
as well as carbocation lifetime and occur at rates much lower than
diffusion.8b–e In contrast, carbocations generated via nitrosoamide
decomposition do not react with saturated solutions of nucleophiles
(including azide).3g In these cases, the carbocation enters into
reaction with solvent at a rate significantly larger than diffusional
encounter with nucleophilic solute.3g In deamination the boundary
conditions on product formation are the very short carbocation
lifetime, the statistical distribution of nucleophiles (solute and
solvent) external to the and the cage effect.3g; (b) J. P. Richard,
Tetrahedron, 1995, 51, 1535; (c) R. A. McClelland, C. Chan,
F. Cozens, A. Modro and S. Steenken, Angew. Chem., Int. Ed. Engl.,
1991, 30, 1337; (d ) J. P. Pezacki, D. Shukla, J. Lusztyk and
J. Warkentin, J. Am. Chem. Soc., 1999, 121, 6589; (e) T. L. Amyes
and J. P. Richard, J. Am. Chem. Soc., 1990, 112, 9507.
11 R. W. Darbeau, G. A. Trahan, L. M. Siso, N. Alvarez, in
preparation.
12 (a) An alternative name for this compound is benzyl N-hydroxy-
carbamate; (b) Early quenching with NaHCO3(aq) was employed to
circumvent acid-catalyzed dealkylations, and disproportionations;
(c) The δ values of 4 and 5 in benzene, toluene, and mesitylene are
4.90, 5.06, 4.79, and 4.31, 4.48, 4.81, respectively.
13 (a) H. Maskill, P. Murray-Rust, J. T. Thompson and A. A. Wilson,
J. Chem. Soc., Chem. Commun., 1980, 788; (b) H. Maskill and
W. P. Jencks, J. Am. Chem. Soc., 1987, 109, 2062; (c) I. M. Gordon
and H. Maskill, J. Chem. Soc., Perkin Trans. 2, 2001, 2059;
(d ) The alcohols used were ethanol, 2,2,2-trifluoroethanol, and
hexafluoropropan-2-ol. The aqueous systems were 1 : 1 (v/v) water :
co-solvent.
14 (a) Similar to the dediazoniation step in the Wolff–Kishner
reduction when the diazenide ion fragments to the alkanide
Ϫ
(RCH2N᎐NϪ
RCH2 ϩ N2); (b) Let kϩ = rate of cationic
᎐
decarboxylation (to 3c) and kϪ = rate of anionic decarboxylation
(to 3d). If kϩ ӷ kϪ, then negligible product from 3d would arise.
If kϩ Ӷ kϪ, then negligible product from 3c would be expected.
Since products from both 3c and 3d are observed then the kϩ ≈ kϪ;
because more 3c-derived product is observed, kϩmust be somewhat
larger than kϪ.
15 (a) K. Lee, B. Gold and S. Mirvish, Mutat. Res., 1977, 48, 131;
(b) R. Preussman and B. W. Stewart, Chemical Carcinogenesis,
C. Searle, Ed., ACS Monograph No. 182, American Chemical
Society, Washington, DC, 1984, pp 643.
16 (a) Beilstein, Vol. 6, p. 221; (b) K. Heyns and W. v. Bebenburg,
Chem. Ber., 1953, 86, 278; (c) Beilstein, Vol. 12, 3rd Suppl.p. 2346;
(d ) G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1963, 296,
57.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 9 5 – 7 0 0
700