Is there stereoelectronic control in hydrolysis of cyclic guanidinium ions?

Article abstract of DOI:10.1021/ja003672y

To assess stereoelectronic effects in the cleavage of tetrahedral intermediates, a series of five-, six-; and seven-membered cyclic guanidinium salts was synthesized. If stereoelectronic control by antiperiplanar lone pairs is operative, these are expected to hydrolyze with endocyclic C-N cleavage to acyclic ureas. However, hydrolysis in basic media produces mixtures of cyclic and acyclic products, as determined by 1H NMR analysis. The results show that in the six-membered ring antiperiplanar lone pairs provide a weak acceleration of the breakdown of the tetrahedral intermediate, but in five- and seven-membered rings there is no evidence for such acceleration, which instead can be provided by syn lone pairs.

Full text of DOI:10.1021/ja003672y

4446
J. Am. Chem. Soc. 2001, 123, 4446-4450
Is There Stereoelectronic Control in Hydrolysis of Cyclic
Guanidinium Ions?
Charles L. Perrin* and David B. Young
Contribution from the Department of Chemistry, UniVersity of California, San Diego,
La Jolla, California 92093-0358
ReceiVed October 13, 2000
Abstract: To assess stereoelectronic effects in the cleavage of tetrahedral intermediates, a series of five-, six-,
and seven-membered cyclic guanidinium salts was synthesized. If stereoelectronic control by antiperiplanar
lone pairs is operative, these are expected to hydrolyze with endocyclic C-N cleavage to acyclic ureas. However,
hydrolysis in basic media produces mixtures of cyclic and acyclic products, as determined by 1H NMR analysis.
The results show that in the six-membered ring antiperiplanar lone pairs provide a weak acceleration of the
breakdown of the tetrahedral intermediate, but in five- and seven-membered rings there is no evidence for
such acceleration, which instead can be provided by syn lone pairs.
Introduction
intermediate (1) is favored when two lone pairs on adjacent Y
Antiperiplanar Lone Pairs. Stereoelectronic control (SELC)
is a topic of much current interest.1 The term refers broadly to
the positioning of lone pairs,2 and it is certainly relevant to
anomeric effects.3 In connection with reactivity it has most
widely been applied at the acetal level of oxidation, but effects
are weak or elusive.4 Consideration here is restricted to a
hypothesis due to Deslongchamps that cleavage of a tetrahedral
atoms are antiperiplanar to the leaving group X.5 This prefer-
ence, often called the antiperiplanar lone-pair hypothesis (ALPH)
or the kinetic anomeric effect, is supported by calculations.6
The role of antiperiplanar lone pairs is a fundamental aspect
of the relationship between molecular structure and reactivity.
It is still an area of considerable uncertainty and controversy,7
with wide acceptance8 and only occasional skepticism.9 Much
of the interest is for purposes of synthesis, where it offers a
novel method to control stereochemistry. Customarily steric
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Komarov, I. V.; Wothers, P. D. J. Chem. Soc., Chem. Commun. 1998, 1695.
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10.1021/ja003672y CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/20/2001

Cyclic Guanidinium Ions
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4447
effects are used to direct an incoming nucleophile along the
least hindered path to create a chiral center selectively. However,
if preferential addition occurs antiperiplanar to a lone pair, this
offers an alternative.10
To what extent is an antiperiplanar lone pair required to
promote cleavage of a tetrahedral intermediate? Certainly an
orthogonal lone pair is much less effective than a periplanar
one.11 The issue remaining is the effectiveness of a syn lone
pair. Early evidence came from the hydrolysis of a cyclic
hemiortho ester (2), which opens exclusively to hydroxy ester,
subsequently found to be due to a disparity in leaving abilities.14
When these are balanced, five- and seven-membered rings
produce considerable lactam 6, counter to ALPH.15 Even in six-
membered rings, where 5 predominates, stereoelectronic control
is weak. It is slightly stronger in methanolysis of six-membered-
ring ortho esters.16
One explanation for these results is the involvement of a syn
lone pair,15 as is supported by computations on acetal hydroly-
sis.17 The proponents of ALPH have accepted the involvement
of synperiplanar lone pairs in some rigid acetals where eclipsing
is obligatory.18 Yet despite numerous counterexamples to
ALPH,19 the proponents continue to reject any general role for
assistance by syn lone pairs in conformationally flexible systems
or in cleavage of tetrahedral intermediates.20 Instead they
maintain that “decomposition of the intermediate is determined
by the orientation of the lone pair orbitals on the heteroatoms,
specific cleavage of a carbon-oxygen or carbon-nitrogen bond
being allowed only if the other two heteroatoms (oxygen or
nitrogen) of the tetrahedral intermediate each have an orbital
oriented antiperiplanar to the leaving O-alkyl or N-alkyl
group”.21
The hypothesis can be extended to reactions with an additional
heteroatom, as in the hydrolysis of guanidinium ions 8. Although
this was thought to proceed by addition of water to the
guanidine,22 the kinetics are equally consistent with rate-limiting
addition of OH-, as in hydrolysis of amidines,23 to form a
tetrahedral intermediate that cleaves as its conjugate base.
Endocyclic C-N cleavage produces acyclic urea 10, whereas
exocyclic cleavage produces cyclic urea 11. In either case the
leaving group is a primary amine CH3NH2 or RCH2NH2, so
leaving abilities are balanced. Furthermore the two sets of
products are matched for stability. The 2-fold statistical bias
toward 10 can be corrected for by expressing the preference
for endocyclic cleavage over exocyclic as [11]/2[10].
rather than lactone.12 This endocyclic C-O cleavage is con-
sistent with a preference for antiperiplanar lone pairs of 3-5
kcal/mol. Nevertheless, a serious inconsistency is that the
corresponding five-membered hemiortho ester (3) also gives
only the hydroxy ester, even though pseudorotation rapidly leads
to a conformer (3′) that has two lone pairs antiperiplanar to the
ethoxy and ought to have cleaved to lactone. Therefore it was
proposed13 that the absence of lactone from 3 must be associated
simply with the well-known destabilization of lactones and of
the transition state leading to them. Moreover, this same
explanation may apply to 2. If so, these product studies are
uninformative regarding the necessity for antiperiplanar lone
pairs.
To provide a more conclusive test of ALPH, hydrolysis of
cyclic amidines was studied. These have the advantage that there
is no bias from product stabilities, since lactams do not share
the destabilization of lactones. Reaction proceeds via a hemi-
orthoamide intermediate, with 4 as the initial conformer. After
rotation about the exocyclic C-N bond, two lone pairs are
antiperiplanar to the endocyclic C-N bond, which can cleave
to form the aminoamide (5). Cleavage of the exocyclic bond
and formation of the lactam (6) could utilize the antiperiplanar
lone pair on O but would require the syn lone pair on the ring
N. In contrast to hemiortho esters (2, 3), although ring inversion
of 4 can produce conformer 7, a second lone pair is not created
antiperiplanar to the exocyclic C-N, so this too cannot cleave
to lactam. Conformers that could cleave to the lactam are
inaccessible because their formation requires nitrogen inversion,
which is slow. Thus if stereoelectronic control is operative, the
aminoamide 5 is predicted to be the kinetic product.
The predictions of ALPH for the behavior of 9 are straight-
forward. According to the principle of microscopic reversibility,
addition of OH- proceeds anti to three nitrogen lone pairs, to
(12) Deslongchamps, P.; Atlani, P.; Fre´hel, D.; Malaval, A.; Moreau,
C. Can. J. Chem. 1974, 52, 3651. Deslongchamps, P.; Cheˆnevert, R.;
Taillefer, R. J.; Moreau, C.; Saunders, J. K. Can. J. Chem. 1975, 53, 1601.
Deslongchamps, P.; Duhe´m S.; Lebreaux, C.; Patterson, D. R.; Taillefer,
R. J. Can. J. Chem. 1975, 53, 2791. Deslongchamps, P.; Lessard, J.; Nadeau,
Y. Can. J. Chem. 1985, 63, 2485.
(13) Perrin, C. L.; Arrhenius, G. M. L. J. Am. Chem. Soc. 1982, 104,
2839.
(14) Perrin, C. L.; Nun˜ez, O. J. Am. Chem. Soc. 1987, 109, 522.
(15) Perrin, C. L.; Nun˜ez, O. J. Am. Chem. Soc. 1986, 108, 5997. Perrin,
C. L.; Thoburn, J. D. J. Am. Chem. Soc. 1993, 115, 3140.
(16) Desvard, O. E.; Kirby, A. J. Tetrahedron Lett. 1982, 23, 4163. Perrin,
C. L.; Engler, R. E. J. Am. Chem. Soc. 1997, 119, 585.
(17) Ratcliffe, A. J.; Mootoo, D. R.; Andrews, C. W.; Fraser-Reid, B. J.
Am. Chem. Soc. 1989, 111, 7661. Andrews, C. W.; Bowen, J. P.; Fraser-
Reid, B. J. Chem. Soc., Chem. Commun. 1989, 1913. Wilson, B. G.; Fraser-
Reid, B. J. Org. Chem. 1995, 60, 317.
(18) Deslongchamps, P.; Jones, P. G.; Li, S.; Kirby, A. J.; Kuusela, S.;
Ma, Y. J. Chem. Soc., Perkin Trans. 2 1997, 2621. Li, S.; Kirby, A. J.;
Deslongchamps, P. Tetrahedron Lett. 1993, 34, 7757. Li, S.; Deslong-
champs, P. Tetrahedron Lett. 1993, 34, 7759.
(19) Somayaji, V.; Brown, R. S. J. Org. Chem. 1986, 51, 2676.
Konstantinidis, A.; Sinnott, M. L. Biochem. J. 1991, 279, 587.
(20) Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta
1992, 75, 604. Deslongchamps, P. Pure Appl. Chem. 1993, 65, 1161.
Deslongchamps, P. In The Anomeric Effect and Associated Stereoelectronic
Effects; Thatcher, G. R. J., Ed.; ACS Symp. Ser.; American Chemical
Society, Washington, DC, 1993; Chapter 3. Deslongchamps, P.; Dory, Y.
L.; Li, S. Heterocycles 1996, 42, 617. Dugas, H. Bioorganic Chemistry,
2nd ed.; Springer: New York, 1989; p 229.
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Saunders, J. K. Can. J. Chem. 1975, 53, 1601.
(22) Homer, R. B.; Alwis, K. W. J. Chem. Soc., Perkin Trans. 2 1976,
781.
In initial studies only endocyclic cleavage was observed,
consistent with ALPH.13 However, the absence of 6 was
(10) Deslongchamps, P. Bull. Soc. Chim. Fr. 1984, II-349. Stevens, R.
V. Acc. Chem. Res. 1984, 17, 289. Kahne, D.; Yang, D.; Lim, J. J.; Miller,
R.; Paguaga, E. J. Am. Chem. Soc. 1988, 110, 8716. Meyers, A. I.; Bienz,
S. J. Org. Chem. 1990, 55, 791. Durkin, K. A.; Liotta, D. J. Am. Chem.
Soc. 1990, 112, 8162.
(11) Briggs, A. J.; Evans, C. M.; Glenn, R.; Kirby, A. J. J. Chem. Soc.,
Perkin Trans. 2 1983, 1637.
(23) Robinson, D. R. J. Am. Chem. Soc. 1970, 92, 3138.

4448 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Perrin and Young
Table 1. Base Solutions
solution
base
[buffer], M
A
B
C
D
E
F
Na3PO4, 1:1
Na3PO4, 25:1
Na3PO4, 80:1
NaOH
NaOH
NaOH
0.16
0.56
1.60
0.050
0.10
1.0
form 12 as initial conformer. Its conjugate base, 12-, might
Therefore only acyclic urea 10 should be produced, if anti-
periplanar lone pairs are required.
undergo C-N cleavage, with prior or simultaneous protonation
of the leaving N. The original formulation of ALPH did not
consider acceleration due to three lone pairs,5 but a logical
extension is that cleavage is favored if there are at least two
lone pairs anti to a leaving group.24 Rotation about the exocyclic
C-N bond produces 13, with two lone pairs antiperiplanar to
the endocyclic C-N bond, which can cleave to produce 10.
Nitrogen inversion in 13 produces 14, with three antiperiplanar
lone pairs, and cleavage again produces 10. Alternatively, ring
inversion of 13 produces 15, also with three lone pairs
We now report that cyclic ureas 11 are nevertheless produced,
especially from five- and seven-membered rings.
Experimental Section
Synthesis. The procedure for synthesis of cyclic guanidinium iodides
is simply methylation of the cyclic thiourea with methyl iodide, followed
by reaction with methylamine.29 The guanidinium iodide, 8‚I- (n )
5), was obtained as a crystalline solid: mp 180-181 °C (lit. mp 178-
1
181 °C); H NMR (D2O) δ 3.68 (s, 4H, CH2), 2.83 (s, 3H, CH3); 13C
NMR (D2O) δ 161.7, 43.6, 29.4.
The six-membered-ring thiouronium iodide30 was converted to the
guanidinium salt by heating for 6 h in 40% aqueous methylamine,
followed by concentration under vacuum. The iodide, 8‚I- (n ) 6),
was obtained as a hygroscopic solid: mp 101-103 °C; 1H NMR (D2O)
δ 3.32 (t, J ) 6 Hz, 4H, CH2(NH)), 2.74 (s, 3H, CH3), 1.92 (q, J ) 6
Hz, 2H, CH2(CH2)2); 13C NMR (D2O) δ 153.8, 38.3, 26.8, 19.6.
The seven-membered-ring thiouronium iodide31 was converted to
the guanidinium iodide, 8‚I- (n ) 7), by refluxing for 6 h in methanol
with excess 40% aqueous methylamine, followed by concentration
under vacuum. A hygroscopic solid was produced: mp 131-132 °C;
1H NMR (D2O) δ 3.24 (m, 4H, CH2(NH)), 2.80 (s, 3H, CH3), 1.66 (m,
4H, CH2(CH2)2); 13C NMR (D2O) δ 161.5, 44.2, 28.3, 26.9.
Sample Preparation. Concentrated (∼1:1 w/v) stock solutions of
salts 8‚I- (n ) 5, 6, 7) in D2O were prepared. Solutions A-F in D2O
with 0.1% tert-butyl alcohol were prepared as listed in Table 1, with
heating if necessary to dissolve. Hydrolyses were carried out quite
conveniently in capped NMR tubes. Each hydrolysis sample was
prepared by adding 10 µL of stock solution to 0.5 mL of reaction
solution, to produce a solution 0.04 M in guanidine. The sample was
shaken to ensure thorough mixing, transferred to an NMR tube, and
placed in an oil bath at 75 ( 2 °C. Samples were heated for g20 h,
then allowed to cool to room temperature before NMR analysis. Each
experiment was performed at least twice. The apparent pH of the
solution was measured before and after hydrolysis.
antiperiplanar to the endocyclic C-N, which again can cleave
to 10. Nitrogen inversion in 15 produces 16, which now has
two lone pairs antiperiplanar to the exocyclic C-N bond and
can cleave to produce 11. Inversion of both nitrogens in 15
produces a conformer 17 that has three lone pairs antiperiplanar
to the exocyclic C-N bond and can also cleave to 11. The time
scale for these processes is limited by the rate constant for
cleavage of a bond anti to two lone pairs, which was estimated
to be 108-109 s-1 25
estimate.15 Rotation about the exocyclic C-N bond is suf-
,
and which is consistent with another
ficiently rapid, with a rate constant of >1010 s-1 26
Rate
.
constants for ring inversion are either slow, 105-106 s-1 for
simple cyclohexanes, or fast, for cyclopentanes and cyclohep-
tanes where this becomes a rapid pseudorotation with a rate
constant >1012 s-1 27
Nitrogen inversion is slow in aqueous
.
solution, with a rate constant near 3 × 105 s-1, depending
somewhat on ring size.28 Therefore during the lifetime of the
intermediate, only conformer 13 is accessible, and also 15 for
n ) 5 or 7. Conformers 16 and 17 are inaccessible because
they require not only ring inversion, which is sufficiently fast
for n ) 5 or 7, but also nitrogen inversion, which is too slow.
To test product stability 2-imidazolidinone or tetrahydro-2-pyrimi-
dinone 10 (n ) 5, 6) was heated at 75 °C with methylamine and NaOH
in D2O for >72 h. Even after 72 h no new NMR signals were observed.
This demonstrates an irreversibility of reaction, which guarantees that
the measured product ratio is a kinetic ratio, not an equilibrium
distribution. Also, hydrolyses in solutions B and E were continued.
After 72 h no new NMR signals were observed, but after several weeks
-
(24) Deslongchamps, P.; Dory, Y. L.; Li, S. Tetrahedron 2000, 56, 3533.
(25) Deslongchamps, P.; Barlet, R.; Taillefer, R. J. Can. J. Chem. 1980,
58, 2167.
(26) Bushweller, C. H.; O’Neil, J. W.; Bilofsky, H. S. J. Am. Chem.
Soc. 1971, 93, 542.
(27) Anet, F. A. L.; Bourn, A. J. R. J. Am. Chem. Soc. 1967, 89, 760.
Allerhand, A.; Gutowsky, H. S. J. Chem. Phys. 1965, 42, 4203. McCullough,
J. P. J. Am. Chem. Soc. 1959, 81, 5884.
(28) Saunders, M.; Yamada, F. J. Am. Chem. Soc. 1963, 85, 1882.
Lambert, J. B.; Keske, R. G.; Carhart, R. E.; Jovanovich, A. P. J. Am. Chem.
Soc. 1967, 89, 3761. Lambert, J. B.; Oliver, W. L., Jr.; Packard, B. S. J.
Am. Chem. Soc. 1971, 93, 933.
signals attributable to H2N(CH2)n-3NH2 and to H2N(CH2)n-3NHCO2
1
(n ) 5, 6, or 7) were detected by H NMR. These are products from
further hydrolysis of the acyclic ureas. The identity of the diamines
was confirmed by addition of authentic samples.
NMR Spectroscopy. All NMR spectra were acquired on a Varian
Unity 500 spectrometer (500 MHz 1H, 125 MHz 13C). Chemical shifts
are reported relative to t-BuOH (δ 1.23 or 31.2).
(29) Aspinal, S. R.; Bianco, E. J. J. Am. Chem. Soc. 1951, 73, 602.
(30) McKay, A. F.; Hatton, J. F. J. Am. Chem. Soc. 1956, 78, 1618.
(31) McKay, A. F.; Kreling, M. E. Can. J. Chem. 1957, 45, 1438.

Cyclic Guanidinium Ions
J. Am. Chem. Soc., Vol. 123, No. 19, 2001 4449
Table 2. Chemical Shift Assignments for Products from
Hydrolysis of 8 (n ) 5, 6, 7)
Table 3. Percent Cyclic Urea from Hydrolysis of 8 at 75 °C
n
solution
% 11
n
solution
% 11
n ) 5
n ) 6
n ) 7
5
5
5
5
5
6
6
7
A
B
C
D
F
A
B
E
38
38
38
38
38
21
11
44
6
6
6
6
7
7
7
C
D
E
F
A
B
D
7.3
11
7.5
5.2
42
51
53
10
11
-CH3
2.66
3.14
2.65
2.66
3.12
1.58
2.60
2.66
3.08
1.41-1.47
1.41-1.47
2.58
-CONHCH2
-CONHCH2CH2
-CONHCH2CH2CHH2
-CONHCH2CH2CH2CH2
-NHCH2
-NHCH2CH2
methylamine
3.51
3.51
2.26
3.25
1.83
2.26
3.12
1.69
2.26
Table 4. Direction of Bond Cleavage in Hydrolysis of 8
n
endo/2exo
5
6
7
0.82
5.5
0.55
Table 2 lists the chemical shifts of products from hydrolyses of 8‚I-
(n ) 5, 6, 7) in solution F. Nearly the same values were obtained in
solutions A-E. Assignments for five- and six-membered-ring cases
were confirmed by addition of authentic 2-imidazolidinone, tetrahydro-
2-pyrimidinone, or methylamine to hydrolysis mixtures. Hydrolysis
products from the seven-membered ring were assigned by analogy to
1,4-diaminobutane and N,N′-dimethylurea and to products from the
other hydrolyses.
cyclic urea is 38% for n ) 5, 5-20% for n ) 6, and 42-53%
for n ) 7. The ratios of endocyclic cleavage to exocyclic,
corrected for statistics, are presented in Table 4.
Both the five- and seven-membered rings yield nearly equal
proportions of cyclic and acyclic ureas. Within experimental
error the product ratios are independent of solution basicity.
The ratio of endocyclic cleavage to exocyclic, corrected for
statistics, is 0.82 or 0.55. This is definitely not a preference for
endocyclic cleavage.
The six-membered ring exhibits the highest selectivity for
endocyclic cleavage over exocyclic. However, this is weak, only
5.5-fold (averaged over the higher pH solutions). Moreover,
there seems to be a decrease in the proportion of cyclic urea at
the highest basicity, in contrast to the other rings.
Integrated intensities of the 1H NMR spectra were used to evaluate
product ratios. Owing to the volatility of methylamine, its integrals
were rejected. When peaks from cyclic and acyclic products overlapped,
integrations from well-resolved peaks were used to determine individual
contributions to the total integral. Ratios are reported as a fraction of
total urea product, to exclude unreacted starting material. This also
neglects any acyclic urea that has undergone further hydrolysis, for
which the resulting signals are too weak to include reliably. Conse-
quently, the apparent yield of cyclic urea was found to increase slightly
at long reaction times, but those data were rejected.
Results
Stereoelectronic Control. In the hydrolysis of these cyclic
guanidines, stereoelectronic control is expected to favor endo-
cyclic C-N bond cleavage to acyclic urea. The data in Table 3
do not show a strong preference for acyclic urea. The data in
Table 4 show a preference for endocyclic cleavage in the six-
membered ring but a slight preference for exocyclic cleavage
in five- and seven-membered rings. This is counter to ALPH.
The exocyclic cleavages to cyclic ureas for n ) 5 or 7 do
not derive from conformers such as 16, since these are
inaccessible during the lifetime of the intermediate. Instead they
derive from conformers such as 12-15. These have no lone
pairs on the ring nitrogens antiperiplanar to the exocyclic C-N
bond. Instead only syn lone pairs are available, and the results
show that they too must be capable of facilitating cleavage.
Therefore anti lone pairs are not required. Indeed, it is well-
known that in five- and seven-membered rings syn eliminations
are quite competitive with anti.32 It is not at all unusual that
syn lone pairs can facilitate cleavage, as was seen with
amidines.15
Stereoelectronic control should not have been expected to
be so universal as to operate even in five- and seven-membered-
ring guanidines. In contrast to six-membered rings, these rings
are flexible enough to allow both synperiplanar and antiperipla-
nar relationships between lone pairs on ring nitrogens and
exocyclic C-N bonds. Besides, the lone pair on a nitrogen of
a nearly planar five-membered ring (18) is not well positioned
to facilitate cleavage of the other endocyclic C-N, because the
orbitals are nearly orthogonal. In the reverse reaction this is a
5-endo-trig ring closure, which is disfavored by Baldwin’s
rules,33 but nevertheless allowed in dioxolane formation.
Reaction Rates. Some qualitative observations regarding
reaction rates could be made. Decreasing the pH by 1 slows all
reactions approximately 10-fold. Reaction becomes unmeasur-
ably slow in carbonate buffers. Among the three guanidines there
is only a slight variation in hydrolysis rate, with n ) 6 reacting
∼10% faster than for n ) 5 or 7. These observations are
consistent with rate-limiting hydroxide attack on the guani-
dinium ion. This step should proceed faster in six-membered
rings because of release of torsional strain.
To determine the effect of basicity, it would be helpful to
know the pH of the various solutions. From the stoichiometries
there is an increase of 2 pH units from D to F. However, the
pH in phosphate buffers is too uncertain, because of incomplete
neutralization of guanidinium ion, the use of D2O at 75 °C, the
effect of ionic strength on the pKa of HPO42-, and the pH
decrease during hydrolysis, owing to conversion of the guanidine
to the less basic amine. Instead the effective basicities were
assessed by comparing reaction rates. After 20 h hydrolysis of
8 (n ) 6) was 65% complete in B, 85% complete in C, 75%
complete in D, and 95% complete in E. These values show
that the basicities of the NaOH solutions and phosphate buffers
overlap. The measured pH values at 25 °C also reflect this.
Product Ratios. The results listed in Table 3 are average
values from repeated experiments. Variations between samples
are generally 1-2% for five- and six-membered rings. In seven-
membered rings signal overlap rendered integrations less
accurate, and product ratios varied by 5-10%.
Discussion
Product Ratios. The key result in Table 3 is that cyclic ureas
are formed in the hydrolysis of 8 (n ) 5, 6, 7). There are
variations in product ratio with ring size. The proportion of
(32) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper & Row: New York, 1987; pp 610-616.
(33) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.

4450 J. Am. Chem. Soc., Vol. 123, No. 19, 2001
Perrin and Young
membered ring. A similar dependence was observed in the
hydrolysis of some amidines.15,35 Since C-N cleavage requires
deprotonation of the hydroxyl, a reduced basicity extends the
lifetime of the intermediate so that ring inversion and nitrogen
inversion become competitive with product formation. Access
to additional conformers such as 16 and 17 then facilitates
exocyclic cleavage. However, this cannot be a major influence,
since the variation is small, only 4-fold across a range of >2
pH units, where the lifetime of the intermediate varies substan-
tially. Moreover, the product ratio from five- and seven-
membered-ring guanidines is constant. In these rings there are
many reactive conformers, where either syn or anti lone pairs
facilitate bond cleavage, so that the lifetime of the intermediate
does not affect its partitioning.
Hydrolyses were also performed in phosphate buffer to test
for bifunctional catalysis. In hydrolysis of imidates, this
promotes C-N cleavage when the OH and the lone pair are
syn,36 which would favor exocyclic cleavage. Yet there is no
appreciable difference between NaOH and a phosphate buffer
of comparable basicity.
In contrast, the endocyclic C-N cleavage in the hydrolysis
of the six-membered ring is consistent with ALPH. This parallels
the strong preference for anti elimination in cyclohexane
derivatives such as menthyl chloride.34 Synperiplanar relation-
ships in six-membered rings are possible only with high-energy
eclipsed conformations. Therefore conformers 12-15 (n ) 6)
do not readily use syn lone pairs to cleave the exocyclic C-N.
Instead they use anti lone pairs to cleave the endocyclic C-N.
Nevertheless, the preference for anti lone pairs, even in this
best case, is weak. The 5.5:1 ratio corresponds to a preference
of only 1 kcal/mol. This is considerably less than the 3-5 kcal/
mol expected from stereoelectronic control.5,12 However, it is
difficult to assess this contribution quantitatively, since there is
also an entropic contribution favoring the cyclic urea, due to
liberation of a molecule of methylamine, and there may be slight
differences in leaving abilities.
Conclusions
The weakness of stereoelectronic control in the six-membered
ring and its apparent absence in five- and seven-membered rings
does not mean that it does not operate. It might be operative in
the cleavage step and not in the addition, or vice versa, as
assumed above. Perhaps addition of OH- syn to both lone pairs
of the ring nitrogens produces 17 directly, or 16 by addition
syn to only one lone pair. These could cleave to 11 with
stereoelectronic control. However, it seems more likely that 11
arises because syn lone pairs are involved in the cleavage of
12-15, formed by addition of OH- anti to lone pairs. The
stereoelectronic selectivity is reduced because the species that
undergoes cleavage is the conjugate base of the intermediate,
derived from 12-. It has an antiperiplanar lone pair on the
oxygen that provides a strong push for elimination. That may
be sufficient so that even syn lone pairs on the nitrogens are
adequate. This is equivalent to assuming that the transition state
is early along the reaction coordinate.20 Such a transition state
resembles the intermediate and has little interaction between
the lone pair and the bond to be cleaved, whose stereochemistry
is then immaterial.
Cyclic urea is formed in the hydrolysis of 8 (n ) 5, 6, 7).
The proportion is 38% for n ) 5, 5-20% for n ) 6, and 47%
for n ) 7. Thus both the five- and seven-membered rings yield
nearly equal proportions of cyclic and acyclic ureas. The
preference, corrected for statistics, is actually for exocyclic
cleavage, and it is counter to ALPH. The six-membered ring
does exhibit a selectivity for endocyclic cleavage over exocyclic,
as expected from ALPH. However, this represents a preference
of only 1 kcal/mol.
The production of cyclic ureas from hydrolysis of these
guanidines is contrary to ALPH. Regardless of whether these
results are interpreted in terms of a reduced selectivity, an early
transition state, or the ready involvement of syn lone pairs, they
show that ALPH has a low predictive power.
Acknowledgment. This research was supported by National
Science Foundation Grant CHE94-20739. Purchase of the 500-
MHz NMR spectrometer was made possible by grants from NIH
and NSF.
JA003672Y
Variation with Basicity. The proportion of counter-ALPH
cyclic urea increases at lower basicity, but only for the six-
(35) Page, M. I.; Webster, P.; Ghosez, L. J. Chem. Soc., Perkin Trans.
2 1990, 805.
(34) March, J. AdVanced Organic Chemistry, 4th ed.; John Wiley: New
York, 1992; pp 983-986.
(36) Perrin, C. L.; Engler, R. E.; Young, D. B. J. Am. Chem. Soc. 2000,
122, 4877.